Cell-intrinsic drivers of dendrite...

© 2013. Published by The Company of Biologists Ltd | Development (2013) 140, 4657-4671 doi:10.1242/dev.087676

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ABSTRACTThe proper formation and morphogenesis of dendrites is fundamentalto the establishment of neural circuits in the brain. Following cell cycleexit and migration, neurons undergo organized stages of dendritemorphogenesis, which include dendritic arbor growth and elaborationfollowed by retraction and pruning. Although these developmentalstages were characterized over a century ago, molecular regulatorsof dendrite morphogenesis have only recently been defined. Inparticular, studies in Drosophila and mammalian neurons haveidentified numerous cell-intrinsic drivers of dendrite morphogenesisthat include transcriptional regulators, cytoskeletal and motorproteins, secretory and endocytic pathways, cell cycle-regulatedubiquitin ligases, and components of other signaling cascades. Here,we review cell-intrinsic drivers of dendrite patterning and discuss howthe characterization of such crucial regulators advances ourunderstanding of normal brain development and pathogenesis ofdiverse cognitive disorders.

KEY WORDS: Cell-intrinsic driver, Dendrite development, Dendritemorphogenesis, Dendrite patterning, Transcription factor, Ubiquitinligases

IntroductionWith their tremendous complexity and diversity, dendrites are oneof nature’s architectural masterpieces. More than a century ago,Ramón y Cajal proposed an important role for dendrites (referred toat that time as protoplasmic processes) as specialized morphologicalstructures that receive neuronal input (Ramón y Cajal, 1995).Further studies using a variety of neuronal cell types (see Glossary,Box 1) have vastly improved our understanding of dendritedevelopment (Scott and Luo, 2001; Grueber and Jan, 2004). Thedevelopment of new approaches for studying dendritemorphogenesis (see Box 2) has led to the view that axons anddendrites work in concert to define neuronal connectivity. A keyconcept that has emerged from such functional studies is that theparticular shapes of dendrites are intimately tied to the proper wiringof neuronal circuits and their function (Häusser et al., 2000; Parrishet al., 2007b; Branco et al., 2010; Branco and Häusser, 2011; Gidonand Segev, 2012; Lavzin et al., 2012).

Prior to the elaboration of dendrites, neurons undergo axo-dendritic polarization, whereby the morphologically and functionallydistinct axonal and dendritic compartments (see Box 3) arespecified. In most neurons, including retinal ganglion neurons,forebrain pyramidal neurons and cerebellar granule neurons, thegeneration of an axon precedes the development and elaboration ofdendrites (Ramón y Cajal, 1995). Although individual neuronal cell

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1Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.2Program in Biological and Biomedical Sciences, Harvard Medical School,Boston, MA 02115, USA. 3Department of Anatomy and Neurobiology, WashingtonUniversity School of Medicine, St Louis, MO 63110, USA.

*Author for correspondence ([email protected])

Cell-intrinsic drivers of dendrite morphogenesisSidharth V. Puram1,2 and Azad Bonni1,2,3,*

Box 1. GlossaryAnterodorsal and lateral projection neurons (aPNs and lPNs). Theseneurons of the Drosophila antennal lobe are crucial for olfactoryprocessing. They receive excitatory input from olfactory receptor neuronsin glomeruli and transmit signals to the mushroom body and lateral horn.Cerebellar granule neurons. The most numerous neurons of the brain,these offer an ideal system for biochemical, morphological andphysiological studies. Granule neurons undergo typified stages ofdevelopment, which can be studied in dissociated culture, slices and invivo. These neurons form specialized structures for synaptic input knownas dendritic claws, which receive inputs from mossy fiber terminals andGolgi neuron axons.Cortical pyramidal neurons. These vary in morphology depending onthe layer they occupy, but typically have a multipolar morphology with asingle apical dendrite, multiple basal dendrites and a single axon. Likegranule neurons, cortical neurons can be studied in dissociated culture,slices and in vivo.Dendritic arborization (da) neurons. These are lateral peripherysensory neurons that cover the Drosophila body wall. They have atypified branching pattern depending on their subtype. Class I daneurons have the simplest arbors, whereas Class IV have the mostcomplex dendritic arbors covering larger dendritic fields. Class-specificvariation allows analysis of the factors driving simple and complexdendritic arbors.External sensory (ES) neurons. These neurons originate from a singleprecursor cell after a series of asymmetrical divisions, ultimately formingthe Drosophila external sensory organ. ES neurons have been used toanalyze the Drosophila peripheral nervous system, and deficits in ESneurons can be studied in behavioral assays.γ neurons. These neurons are found in Drosophila mushroom bodies(structures involved in olfactory memory). During the first day of pupallife, γ neuron dendrites undergo extensive degeneration with loss ofdendrites branching into the larval vertical and medial lobes. Dendritesthen regrow as adult projection patterns are established.Hippocampal pyramidal neurons. These neurons have numeroussynaptic inputs and specialized protrusions known as dendritic spinesalong their dendrite shafts. They have been used for electrophysiologyand morphology studies, although analyses typically require methodssuch as Scholl analysis because of the density of dendrites.Multidendritic (md) sensory neurons. Also known as type II neuronsof the peripheral nervous system, these are divided into three subtypes:tracheal dendrite (md-td), bipolar dendrite (md-bd) and dendriticarborization (da). They are located along the body wall, where they serveas touch receptors and proprioceptors.Optic tectal neurons. Xenopus optic tectal neurons receive andintegrate visual as well as auditory, somatosensory and vestibular inputs.In addition to electrophysiological analyses, these neurons can easily belabeled and visualized in vivo allowing time-lapse studies of dendritemorphogenesis.Retinal ganglion cells (RGCs). These neurons are located in theganglion cell layer of the retina, which receives inputs from bipolar andamacrine cells. The primary output of these cells is to higher ordercenters in the brain, such as the thalamus and hypothalamus, as well asmidbrain structures.Vertical system neurons. These are present in the lobula plate of theDrosophila optic lobe, where they are responsible for motion detectionand stabilization reflexes during flight. They have a complex and highlyelaborate set of dendrites and an axon that travels medially towards theesophagus.

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types have specific programs of dendrite development, the criticalsteps in dendrite morphogenesis can be broadly defined (Fig. 1).

First, dendrites extend away from the soma into their target fieldusing guidance cues to steer towards or away from their targets.During this time, dendrites grow and attain length, diameter, growthrate and molecular characteristics that are distinct from those ofaxons (Craig and Banker, 1994). Second, as dendrites grow fartheraway from the soma, branching is necessary to cover the target field.Dendrites can branch numerous times, with extensive secondary andtertiary branching. Dendrite branching occurs primarily viainterstitial branching, whereby branches emerge from the side ofexisting dendrite shafts; branches initially appear as filopodia thenmorph into growth cone-like structures and extend to become stablebranches (Dailey and Smith, 1996). Third, dendrite growth isrestrained as the dendrite arbor reaches defined borders, giving riseto the mature shape of the dendritic tree (Wässle et al., 1981; Gaoet al., 1999). For example, retinal ganglion cells (RGCs, seeGlossary, Box 1) stop growing upon contact with neighboring RGCsof the same type (Wässle et al., 1981), allowing each functionalgroup of RGCs to non-redundantly cover the entire retina. Suchdendritic tiling occurs in diverse populations of neurons (Perry andLinden, 1982; Kramer and Kuwada, 1983; Amthor and Oyster,1995; Grueber et al., 2002; Sagasti et al., 2005; Millard andZipursky, 2008; Huckfeldt et al., 2009) and is induced by repulsiveinteractions between dendrites of the same neuron type. In somesystems, dendritic fields may be spatially restricted to a two-dimensional plane, thereby facilitating these repulsive contacts (Hanet al., 2012). Self-avoidance ensures that dendritic branches of thesame neuron spread out evenly within a territory (Corty et al., 2009).In other neurons, such as Drosophila motoneurons, dendrites havea domain organization that relies on molecular boundaries defined

during segmentation of the embryo (Landgraf et al., 2003). Together,these mechanisms of dendritic tiling and self-avoidance are essentialfor limiting dendrite growth and establishing non-redundantcoverage of distinct territories. Fourth, dendrites differentiate anddevelop specialized structures that house synapses. In hippocampalpyramidal neurons (see Glossary, Box 1), dendrites generate smallspecialized protrusions termed dendritic spines (Peters et al., 1991),whereas in cerebellar granule neurons (see Glossary, Box 1)dendrites form cup-like structures termed dendritic claws at theirends (Palay and Chan-Palay, 1974). These steps in dendritepatterning are necessary for the accurate formation of neuronalcircuitry. Finally, dendrite pruning is an important step inestablishing the mature dendritic arbor. In Drosophila, dendrites canundergo substantial remodeling during metamorphosis from larva toadults. These changes occur through programmed degeneration ofthe dendrite arbor, with molecular pathways governing thefragmentation of dendrites and clearance by phagocytosis (Williamsand Truman, 2005). The soma then undergoes a process whereby anew dendritic arbor is regrown. By contrast, pruning in mammalianneurons refers to the modification of arbors via retraction andelimination of dendrite branches. For example, in the rodentcerebellum, following the stage of exuberant arbors, dendrites are

REVIEW Development (2013) doi:10.1242/dev.087676

Box 2. Techniques and culture systems for studyingdendrite morphogenesisSingle-cell labeling in combination with genetic manipulation in severalculture systems and organisms has been used to assess gene functionin neurons. In particular, methods including biolistic transfection(Karlsgodt et al., 2008), DiI labeling (Arnold et al., 1994; Lo et al., 1994)and viral transfection (Gan et al., 2000) have facilitated studies ofdendrite development. In addition, expression of genes/markers fromspecific promoters has been used to visualize subpopulations of neurons(Nedivi et al., 1998). Genetic mosaic methods have been used to labeland genetically manipulate individual neurons (Gao et al., 1999;Holtmaat et al., 2009).

Many studies have been carried out in Drosophila due to the well-characterized nature of specific neuron populations, the ability to carryout forward genetic screens, and the ease of studying unique aspects ofdendrite morphogenesis. C. elegans also offers an elegant system forgenetic studies of proteins involved in dendrite morphogenesis, andseveral major findings in the field have originated in nematodes.However, the characterization of dendrite morphogenesis in specificneuronal populations in nematodes lags behind that of flies andmammals. The vast majority of studies in mammalian systems havebeen carried out in rodents, including mice and rats, mostly usingcortical, hippocampal or cerebellar granule neurons. All three populationscan be studied in dissociated cultures or using an ex vivo approach withslice cultures, as well as in vivo using electroporation, viral transductionor genetic knockouts. Furthermore, behavioral assays in mammaliansystems offer the advantage of studying the complex behaviors andpathologies seen in humans. However, compared with Drosophila andC. elegans, characterizing the regulators of dendrite morphogenesis inmammals and their effects on behavior and neuronal connectivity aretechnically more arduous and time consuming. Thus, the combination ofDrosophila, C. elegans and mammalian systems offers a complementaryapproach to the study of dendrite morphogenesis.

DifferentiationGrowth/branching PruningSpecification

Fig. 1. Critical stages of dendrite morphogenesis in mammalianneurons. The morphogenesis of granule neuron dendrites in the cerebellarcortex, like that of dendrites in other areas of the brain and in otherorganisms, occurs via distinct stages mediated by a variety of molecularregulators. After exiting the cell cycle, neural progenitors undergopolarization, whereby an axon is specified and subsequently extends, andthis is followed by the specification of additional processes as dendrites.Dendrite morphogenesis then begins with dendrite growth and branching.Exuberant dendrite arbors are then pruned with the elimination of someprocesses but not others, yielding the dendrites that will persist afterdevelopment. These remaining dendrites undergo a process of differentiationand maturation, whereby they develop specialized structures suited to theformation of synapses and contact with axons. Although the exact order ofthese steps and their timing varies between individual neuronal types andorganisms, these fundamental steps are generally conserved. The imageshown depicts granule neurons of the rat cerebellar cortex at distinct stagesof dendrite development as initially drawn and characterized by Ramón yCajal (Ramón y Cajal, 1995). In the last stage, specialized structures forsynaptic input known as dendritic claws are pictured as cup-like extensionsat the ends of the dendrites.

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pruned to establish their mature shape and subsequently undergopostsynaptic differentiation (Ramón y Cajal, 1995; Okazawa et al.,2009). The process of pruning may therefore ensure that onlydendrites that are properly innervated undergo maturation (Wingateand Thompson, 1994; Wong et al., 2000; Ramos et al., 2007).

The molecular mechanisms regulating dendrite morphogenesiscan be broadly divided into cell-extrinsic and cell-intrinsicmechanisms. Chemoattractive and chemorepulsive cues, such asephrins, semaphorins and neurotrophins, are important examples ofcell-extrinsic regulators of dendrite morphogenesis (Whitford et al.,2002; Jan and Jan, 2003; Miller and Kaplan, 2003; Kim and Chiba,2004). Cell-intrinsic control refers to mechanisms that do not strictlydepend on external cues, although external cues may influence theiractivity (Goldberg, 2004; Kim and Bonni, 2007; Stegmüller andBonni, 2010; Yang et al., 2010; de la Torre-Ubieta and Bonni, 2011;Puram and Bonni, 2011; Yamada et al., 2013). The cell-extrinsicregulators of dendrite morphogenesis, including cell surfacereceptors and other membrane-bound proteins, have been reviewed(Scott and Luo, 2001; Whitford et al., 2002; Grueber and Jan, 2004;Konur and Ghosh, 2005; Corty et al., 2009) and will not bediscussed here. Rather, we focus our attention on the major cell-intrinsic mechanisms, namely the regulators operating within thecell downstream or independently of cell surface receptors and otherneurons, and their role in dendrite morphogenesis in bothinvertebrates and mammals. In doing so, we provide acomprehensive review of dendrite biology, offering insights intopotential areas of future investigation and conveying broader themeswithin the field.

The importance of cell-intrinsic control of dendritepatterningDuring development, different neuronal cell types encounter similarenvironmental factors. However, intrinsic pathways within eachneuron control the cellular interpretation of these extrinsic cues, thusallowing neurons to generate distinct patterns of dendritedevelopment. For example, distinct cortical pyramidal neurons (seeGlossary, Box 1) respond differently to the same neurotrophin:exposure of cortical slices to neurotrophin 4 (NT-4, or Ntf4) inducesdendrite arborization and complexity in layer V pyramidal neurons,but has little or no effect on layer IV neurons (McAllister et al.,1995), whereas brain-derived neurotrophic factor (BDNF) stronglystimulates dendrite growth in layer IV neurons with moderate effectson layer V neurons. Distinct neurotrophin receptor expressionpatterns may thus explain the unique response of each cortical layer

to different neurotrophins, highlighting that cell-intrinsicmechanisms determine the neuronal response to particular extrinsiccues in the environment.

In addition to controlling the specificity of dendrite patterning,cell-intrinsic mechanisms also coordinate the timing of dendritemorphogenesis. Neonatal RGCs rapidly lose the ability to extendaxons upon the onset of dendrite development (Goldberg et al.,2002; Goldberg, 2004). Furthermore, RGCs from postnatal day (P)8 animals extend significantly more dendrites than RGCs culturedfrom embryonic day (E) 20 animals under identical cultureconditions, suggesting that a precisely timed cell-intrinsic programenables neurons to rapidly develop and elaborate dendrites.Together, these studies demonstrate the important role of cell-intrinsic regulators in defining neuronal responses to extrinsic cuesand driving dendrite patterning in the nervous system.

Transcriptional control of dendritic patterningTranscriptional regulators contribute to the specification ofneuronal dendrite arbors. In some cases, distinct dendritemorphology can be attained by varying the levels of a singletranscriptional regulator, whereas in other cases multipletranscriptional regulators operate synergistically to define dendritearbors. As we discuss below, studies in both flies and mammalshave identified a number of transcription factors that can positivelyand negatively regulate distinct aspects of dendrite morphogenesis(summarized in Table 1).

Insights from flies: individual and combinatorial actions oftranscription factors regulate dendrite patterningStudies of the Drosophila peripheral nervous system have revealedthat transcription factors can induce dramatic changes in dendritepatterning. For example, Jan and colleagues identified the zinc-finger (ZnF)-containing transcription factor Hamlet as a keyregulator of dendrite branching (Moore et al., 2002). In loss-of-function hamlet mutants, the single, unbranched dendritic arbor ofexternal sensory (ES) neurons (see Glossary, Box 1) mimics thehighly branched arbor that is characteristic of multidendritic (md)sensory neurons (see Glossary, Box 1). Expression of Hamlet in mdneuron precursors has the opposite effect, yielding dendritemorphologies similar to those of ES neurons. Together, thesefindings emphasize that a single transcription factor can drive celltype-specific differentiation and dendrite arborization.

Forward genetic screens in Drosophila class I dendriticarborization (da) neurons (see Glossary, Box 1) have identified morethan 70 transcription factors that may control dendrite growth(Parrish et al., 2006). Among these, a gene encoding the BTB-ZnFprotein Abrupt is uniquely expressed in class I da neurons. Ectopicexpression of Abrupt in other classes of da neurons reduces theircomplexity and size, suggesting that Abrupt limits dendrite growthand elaboration in class I da neurons (Li et al., 2004; Sugimura etal., 2004). By contrast, the homeodomain-containing transcriptionfactor Cut is expressed at different levels in class I, II, III and IV daneurons; the four classes exhibit undetectable, low, medium andhigh levels of Cut expression, respectively (Blochlinger et al., 1990;Grueber et al., 2003). Strikingly, loss-of-function cut mutations inneurons that normally express cut causes simplification of dendrites,whereas overexpression of cut in class I neurons switches arborstoward the dendrite pattern of class III neurons (Grueber et al.,2003). Cut appears to induce actin-rich filopodia-like protrusionsthat may influence branch dynamics and allow neurons to elaboratemore complex dendritic trees. Like Cut, the bHLH-PAStranscription factor Spineless is expressed in all four classes of da

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Box 3. Structurally and functionally defining axons anddendritesNeuronal polarization follows a strictly orchestrated and tightly controlledsequence of events (Lee and Luo, 1999; Barnes and Polleux, 2009), withdistinct axonal and dendritic compartments defined by much more thantheir functional differences as the output and input processes,respectively, of the neuron. Structurally, dendrites are supported by anintricate scaffold of microtubules and filamentous actin (F-actin).Microtubules fill the interior of dendrites providing structural integrity,while F-actin is distributed along the cortex (Tahirovic and Bradke, 2009;Cáceres et al., 2012). In mammalian neurons, the structural protein Tau-1 (also known as Mapt) is typically localized in axons, whereas dendritescan be identified based on enrichment of microtubule-associated protein2 (Map2) (Peters et al., 1991). Furthermore, in contrast to axons, whichhave unidirectional plus-end-distal microtubules, dendrites have bothplus- and minus-end-distal populations (Baas et al., 1991; Baas and Lin,2011). Thus, structural as well as functional differences define the distinctaxonal and dendritic compartments in neurons.

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neurons. Spineless appears to enable dendrite diversification,perhaps by endowing da neurons with the ability to respond to othertranscription factors and signaling molecules. spineless mutant flieshave more complex class I and II da neurons, whereas class III andIV da neurons develop simpler dendritic arbors (Kim et al., 2006).

Transcription factors have also been implicated in dendriticpatterning in the Drosophila olfactory system, in which distinct celllineages non-redundantly target their dendrites to specific glomeruli.For example, in addition to specifying da neuron arborization, Cut hasalso been implicated in dendrite targeting in the Drosophila olfactorysystem (Komiyama and Luo, 2007). The POU homeodomaintranscription factors ACJ6 and Drifter (also known as Ventral veinslacking) also appear to define the specificity of dendrite targeting inanterodorsal and lateral projection neurons (aPNs and lPNs,respectively, see Glossary, Box 1). Misexpression of Drifter in aPNs,which normally express ACJ6, or misexpression of ACJ6 in lPNs,which normally express Drifter, causes dendrites to target the incorrectglomeruli, suggesting that these transcription factors specify dendritetargeting in these neurons (Komiyama et al., 2003). More recentstudies have identified a role for the BTB-ZnF transcription factorLola, the chromatin remodeling factor Bap55 operating through theTIP60 complex, and the histone deacetylase Rpd3 acting via thetranscription factor Prospero in the wiring and targeting of Drosophilaolfactory projection neurons (Komiyama and Luo, 2007; Spletter etal., 2007; Tea et al., 2010; Tea and Luo, 2011).

Transcription factors may also function in a combinatorial fashionto specify dendrite patterning (Corty et al., 2009). The transcriptionfactor Knot (also known as Collier) is expressed specifically in classIV da neurons of Drosophila, where it suppresses Cut-inducedfilopodia-like protrusions (Hattori et al., 2007; Jinushi-Nakao et al.,2007; Crozatier and Vincent, 2008). The combined expression ofCut and Knot is essential for the correct patterning of class IV daneurons. By contrast, Cut but not Knot is expressed in class IIIneurons, which uniquely harbor actin-rich terminal branchletsknown as spiky protrusions. These terminal branchlets can bespecifically marked by Fascin (also known as Singed), which is alsorequired downstream of Cut for these spiky protrusions to formcorrectly (Nagel et al., 2012). Thus, the pattern of expression of Cutand Knot dictates neuronal type-specific dendrite morphology.

Together, these studies in Drosophila establish the theme thatindividual transcription factors, acting either alone or in combinationwith other transcription factors, may drive specific aspects ofdendrite patterning and arborization in a cell type-specific manner.

Transcriptional control of dendrite morphogenesis in the mammalianbrainA few of the transcriptional regulators of dendrite morphogenesis inDrosophila appear to have conserved functions in mammalianneurons. Mammalian orthologs of Cut, termed Cut-like 1 and 2(Cux1 and Cux2), have been characterized and may have conservedfunctions in dendrite morphogenesis. In mammalian corticalpyramidal neurons, Cux1 but not Cux2 appears to reduce dendritecomplexity by suppressing the expression of p27Kip1 (also knownas Cdkn1b) and regulating RhoA (Li et al., 2010b). Other studiessuggest that Cux1 and Cux2 operate in a cell-intrinsic manner tostimulate the growth and branching of dendrites in upper layercortical neurons (Cubelos et al., 2010). In addition to Cux1 andCux2, other homologs of Drosophila have been identified inmammals. However, many of these, such as the Spineless homologaryl-hydrocarbon (dioxin) receptor (AHR), have undefined roles indendrite morphogenesis in mammals (Hahn, 2002).

Several transcription factors have been implicated in dendritemorphogenesis in the mammalian brain (Gaudillière et al., 2004;Hand et al., 2005; Shalizi et al., 2006; Ramos et al., 2007; Shalizi etal., 2007; de la Torre-Ubieta et al., 2010). An overarching principle ofthese studies is that distinct transcription factors may be dedicated todifferent phases of dendrite development. For example, de la Torre-Ubieta et al. identified a crucial role for the brain-enriched FOXOtranscription factor Foxo6 in the establishment of neuronal polarity(de la Torre-Ubieta et al., 2010; Christensen et al., 2011). In bothprimary cerebellar granule and hippocampal neurons, as well as in thecerebellar cortex in vivo, knockdown of FOXO proteins leads to anunpolarized neuronal morphology. Foxo6 directly stimulates theexpression of Pak1, which then acts locally to promote neuronalpolarization (Bokoch, 2003; Jacobs et al., 2007; Causeret et al., 2009).At later stages of neuronal morphogenesis, Foxo6 inhibits the growthof differentiated dendrites, thereby contributing to the characteristicmorphology of neurons with long axons and shorter dendrites. In


Table 1. Transcriptional regulators of dendrite morphogenesisTranscriptional regulator Organism (cell type) Function Key studies

Hamlet Drosophila (ES neurons) Cell type-specific arborization Moore et al., 2002Abrupt Drosophila (da neurons) Limits arborization Li et al., 2004; Sugimura et al., 2004Cut (Cux1) Drosophila (da and olfactory neurons) Growth and elaboration of arbors; Blochlinger et al., 1990; Grueber et al.,

dendrite targeting 2003; Komiyama and Luo, 2007Knot Drosophila (da neurons) Cell type-specific arborization Hattori et al., 2007; Jinushi-Nakao et al.,

2007Spineless [aryl-hydrocarbon Drosophila (da neurons) Dendrite diversification Kim et al., 2006; Hahn, 2002

(dioxin) receptor]ACJ6 and Drifter Drosophila (olfactory aPNs and lPNs) Dendrite targeting Komiyama et al., 2003Foxo6 and neurogenin 2 Mammals (hippocampal, pyramidal and Control of neuronal polarization and de la Torre-Ubieta et al., 2010; Hand et

cerebellar granule neurons) dendrite growth al., 2005NeuroD Mammals (cerebellar granule neurons) Dendrite growth and elaboration Gaudillière et al., 2004CREB Mammals (cortical neurons) Dendrite growth Redmond et al., 2002; Dijkhuizen and

Ghosh, 2005; Chen et al., 2005CREST Mammals (hippocampal and cortical Dendrite growth and elaboration Aizawa et al., 2004; Wu et al. 2007

neurons)Sp4 Mammals (cerebellar granule neurons) Limits dendrite arborization and Ramos et al., 2007; Ramos et al., 2009

promotes pruningMEF2A Mammals (cerebellar granule and Postsynaptic dendrite differentiation Shalizi et al., 2006; Flavell et al., 2006

hippocampal neurons)

Known homologs are listed in parentheses following the transcription factor name.

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other studies, the bHLH transcription factor neurogenin 2 (Ngn2) hasbeen implicated in the specification of unipolar apical dendritemorphology in cortical pyramidal neurons (Hand et al., 2005).Expression of wild-type Ngn2, but not the Y241F phosphorylationmutant, induces multipolar dendrite morphology with no apicaldendrite, suggesting that Tyr241 phosphorylation is required for Ngn2to regulate dendrites. Together, these findings establish transcriptionalmechanisms that both control the specification of dendrites andlicense further steps in dendrite development.

The bHLH transcription factor NeuroD also stimulates dendritegrowth and arborization (Gaudillière et al., 2004). Knockdown ofNeuroD in primary cerebellar granule neurons and organotypiccerebellar slices dramatically reduces dendrite growth andarborization, but does not inhibit the growth of axons. The functionof NeuroD in dendrite growth persists into adulthood, as shown foradult-born granule neurons of the hippocampus in NeuroD(Neurod1) knockout mice (Gao et al., 2009). Granule neurons fromNeuroD null mice have significantly shorter dendrites than neuronsfrom wild-type animals. Together, these findings establish anessential function for NeuroD in dendrite morphogenesis.

Transcriptional mediators of activity-dependent dendritemorphogenesisInterestingly, NeuroD activity appears to be regulated by calciumsignaling and neuronal activity (Fig. 2). The activity-regulated

protein kinase CaMKIIα stimulates NeuroD phosphorylation atSer336, thereby triggering NeuroD-dependent transcription anddendrite growth (Gaudillière et al., 2004). Accordingly, disruptionof NeuroD largely abrogates the effects of CaMKIIα on dendritedevelopment. Thus, NeuroD acts downstream of neuronal activityto regulate dendrite elaboration. However, the transcriptional targetsof NeuroD that mediate these effects on dendrite morphogenesisremain to be elucidated.

Like NeuroD, the transcription factor cAMP responsive elementbinding protein (CREB) mediates activity-dependent dendritemorphogenesis in mammalian brain neurons (Fig. 2) (Dijkhuizen andGhosh, 2005). In addition to the protein kinase CaMKIV, the smallGTP-binding protein Rap1 appears to contribute to calcium-dependentactivation of CREB signaling, suggesting that multiple pathwaysmight link calcium influx with CREB-dependent transcription anddendrite growth (Chen et al., 2005). Expression of dominant-negativeCREB suppresses voltage-gated calcium channel- and CaMKIV-induced dendrite growth (Redmond et al., 2002), suggesting thatCREB-dependent transcription is required for activity-dependentdendrite growth and that CREB acts as a node in activity-dependentsignaling. Although the specific targets of CREB that control dendritegrowth remain to be fully characterized, BDNF has been identified asone target that promotes dendrite growth in both cortical andcerebellar neurons (McAllister et al., 1995; McAllister et al., 1996;Schwartz et al., 1997; Horch et al., 1999; Mertz et al., 2000).

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VSCCs or NMDARs

Ca2+

CytoplasmCytoplasm

Nucleus

CBP

CaMKK

A B

BAF53BBAF Complex

CREB

CaMKIIα

CaMKIγ

NeuroD

PP-Bdnf-Wnt2-Cpg15-Other genes

Ca2+

TRPC5

CentrosomeCaMKIIβ

Proteins regulatingdendrite retraction

Dendrite growthand elaboration

Cdc20-APC

P

Id1

P

P

CREST

NeuroD

CREB

CaMKIV

Fig. 2. Calcium-mediated regulation of dendrite morphogenesis. Calcium-regulated control occurs throughout dendrite morphogenesis – during growthand elaboration as well as during dendrite pruning and retraction. (A) Neuronal depolarization with subsequent calcium entry via voltage-sensitive calciumchannels (VSCCs) or NMDA receptors (NMDARs) triggers the activation of calcium/calmodulin-dependent kinase (CaMK) family members, thereby directingtranscription factor activity in the nucleus. CREB functions downstream of CaMKIγ or CaMKIV, while the transcription factor NeuroD is phosphorylated andactivated by CaMKIIα. Other transcriptional regulators such as CBP bind to CREB and influence transcription. At the level of chromatin, the chromatinremodeling complex nBAF plays a role in regulating activity-dependent dendrite growth. CREST binds to the nBAF complex and, in turn, controls geneexpression. Together, these diverse mechanisms provide complex, yet tightly regulated, control of gene expression relevant for dendrite growth, including Bdnf,Wnt2 and Cpg15 (Nrn1). (B) During later stages of dendrite development, calcium regulates ubiquitin signaling at the centrosome to drive dendrite retractionand pruning. Calcium influx via the membrane channel TRPC5 activates CaMKIIβ, which phosphorylates and inhibits the major ubiquitin ligase Cdc20-APC atthe centrosome. As a result, the Cdc20-APC substrate Id1 accumulates at the centrosome leading to dendrite retraction and pruning.

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The SYT-related nuclear protein calcium-responsive transactivator(CREST, also known as Ss18l1) also mediates calcium-induceddendrite growth (Fig. 2). Using a transactivator trap approach,Ghosh and colleagues identified CREST as a key downstreameffector of calcium influx (Aizawa et al., 2004). Crest knockoutmice have impaired dendrite growth in the cortex and hippocampus,and cortical neurons cultured from these mice fail to elaboratedendrites in response to neuronal activity. CREST operates as atranscriptional regulator, and studies from Crabtree and colleaguesrevealed that CREST binds to subunits of the neuron-specificchromatin remodeling Brg/Brm-associated factor complex (nBAF)to drive activity-dependent dendrite growth (Wu et al., 2007).CREST and nBAF interact in neurons, where, in combination withthe key subunit nBAF53b (also known as Actl6b), they control theexpression of genes involved in neuronal morphogenesis. UsingBaf53b knockout mice, Gap43, Stmn2, Rap1a, Gprin1 and Ephexin1(also known as Ngef) were identified as targets of this complex.Expression of Ephexin1 corrected dendrite defects in Baf53bknockout neurons and reversed their impairment in activity-dependent dendrite growth (Wu et al., 2007), consistent with a roleof Ephexin1 in balancing Rho and Rac/Cdc42 signaling (Shamah etal., 2001; Sahin et al., 2005). Several homologs of nBAF have beenidentified in Drosophila as important regulators of dendritedevelopment (Parrish et al., 2006), suggesting that this signalingpathway might be conserved.

As dendrites are pruned, they begin to form postsynapticstructures specialized for contact with axons. In the cerebellum, forexample, granule neurons form cup-like structures called dendriticclaws (Hámori and Somogyi, 1983). One transcription factorimplicated in dendrite differentiation is myocyte enhancer factor 2A(MEF2A). Knockdown analyses reveal that MEF2A is required forthe morphogenesis of dendritic claws in the cerebellar cortex in vivo(Shalizi et al., 2006). Neuronal activity stimulates calcineurin, whichinduces the dephosphorylation of MEF2A at Ser408 and promotesa sumoylation-to-acetylation switch at Lys403, thereby activatingMEF2A and inhibiting dendritic claw differentiation. The SUMO E3ligase PIASx (also known as Pias2) induces MEF2 sumoylation andconsequently stimulates dendritic claw differentiation in thecerebellar cortex in vivo (Shalizi et al., 2007). Biochemical andnuclear magnetic resonance (NMR) structural studies suggest thatSer408 phosphorylation stimulates the ability of the SUMO E2enzyme Ubc9 (also known as Ube2i) to trigger SUMO conjugationat Lys403 (Mohideen et al., 2009). These findings establish acalcium-regulated MEF2 sumoylation switch that transcriptionallycontrols dendrite differentiation. Although several transcriptionfactors have emerged as key regulators of dendrite patterning ininvertebrates and mammals, it will be essential to understand howthese distinct pathways are ultimately integrated to sculpt the maturedendrite arbor.

Role of other transcriptional regulatorsIn granule neurons of the cerebellar cortex, the transcriptionalregulator SnoN (also known as Skil) controls neuronal branching,including dendrite branching, in an isoform-specific manner (Huynhet al., 2011). In Drosophila, polycomb proteins, which are broadlyinvolved in transcriptional silencing, have been implicated in themaintenance of Drosophila sensory neuron dendrites (Parrish et al.,2007a).

Transcription factors may also repress dendrite branching. TheZnF transcription factor Sp4, for example, has been implicated inthe patterning of granule neuron dendrites (Ramos et al., 2007).Knockdown of Sp4 in primary granule neurons and in organotypic

cerebellar slices leads to the exuberant branching of dendrites(Ramos et al., 2007). In addition, activity-induced dendriticremodeling is blocked by Sp4 knockdown, suggesting that Sp4might restrict branch formation and promote activity-dependentpruning. Follow-up studies revealed that Sp4 binds to the promoterof neurotrophin 3 (NT-3, or Ntf3) and represses its activity, therebyreducing NT-3 expression and limiting dendrite branching inneurons (Ramos et al., 2009). Thus, distinct transcription factorsmay positively or negatively regulate dendrite arborization in themammalian brain, offering a highly specific but complex layer ofcontrol over dendrite morphogenesis.

The role of steroid hormonesLike transcription factors, steroid hormones operate in the nucleusto regulate dendrite development. The γ neurons of the Drosophilamushroom body (see Glossary, Box 1), for example, appear to bedifferentially regulated by the nuclear receptor Ftz-f1 and itshomolog Hr39 (Boulanger et al., 2011). Although these analysesprimarily focused on axonal pruning and remodeling, the authorssuggest a role for Ftz-f1 in triggering expression of the steroidhormone receptor Ecr-B1 and downregulating expression of Hr39,thereby inducing pruning of γ neuron dendrites. By contrast, Hr39competes with endogenous Ftz-f1 and thereby decreases Ecr-B1levels to disrupt pruning. Thus, Ftz-f1 and Hr39 exert opposingeffects on dendrite arbors by acting as a rheostat for Ecr-B1expression. Furthermore, recent studies of Drosophila da neuronssuggest that, in the presence of the steroid hormone ecdysone, Ecr-B1 binds to CREB-binding protein (CBP) and, in collusionwith the epigenetic factor Brm, induces the acetylation of H3K27at the Sox14 gene locus (Kirilly et al., 2011). Thus, steroidhormones may operate through epigenetic mechanisms to regulatedendrite morphogenesis, although the biochemical links remainunknown.

Cytoskeleton-mediated control of dendritic morphogenesisCytoskeletal regulators act on structural proteins within the somaand dendrites to control dendrite morphogenesis throughoutdevelopment. Early in development, these regulators drivefundamental changes in dendrite growth and arborization, whereasat later stages they provide mechanisms for the finely tuned controlof the dendrite arbor. By restructuring the actin and microtubuleskeleton, these regulators can mediate direct changes in dendritearborization and length.

Rho family GTPases and actin cytoskeletal regulatorsThe Rho family of GTPases modulates the cytoskeleton to regulatedendrite growth and branching in invertebrate and mammalianneurons (Leemhuis et al., 2004; Newey et al., 2005; Chen andFirestein, 2007). These proteins cycle between an activated GTP-bound state and an inactive GDP-bound state. The small GTPaseRhoA limits dendrite growth, whereas Ras-related C4 botulinumtoxin substrate 1 (Rac1) and Cdc42 appear to drive dendriteelaboration (Scott and Luo, 2001). Constitutively active RhoAexpression in Drosophila central nervous system neurons, XenopusRGC and central neurons, chick RGC explants, and rat hippocampalslices reduces dendrite length and the volume of the dendritic field(Ruchhoeft et al., 1999; Lee et al., 2000; Li et al., 2000; Nakayamaet al., 2000; Wong et al., 2000). RhoA loss-of-function mutations inflies cause mushroom body neurons to overshoot their boundaries,leading to abnormal dendritic fields (Lee et al., 2000). In contrast toRhoA mutants, loss of Rac1 in flies reduces dendrite complexity andsize in mushroom body neurons (Ng et al., 2002). Similarly, in larval


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class IV da neurons, Rac1 and the actin-stabilizing proteintropomyosin regulate dendrite growth and branching (Lee et al.,2003; Li and Gao, 2003). Loss of Cdc42 in vertical system neurons(see Glossary, Box 1) of the Drosophila visual system interfereswith typical branching patterns and tapering of dendrites (Scott etal., 2003), whereas hyperactivation of Cdc42 in mice bearingmutations in the Cdc42 GAP NOMA-GAP (also known asArhgap33) leads to simplified cortical dendrites in vivo by regulatingthe actin regulator cofilin (Rosário et al., 2012). In other systems,including Xenopus optic tectal neurons (see Glossary, Box 1) andmammalian RGCs, Rac1 and to a lesser extent Cdc42 selectivelyincrease dendrite branch extension and retraction (Li et al., 2000;Wong et al., 2000).

How might Rho and Rac activity be regulated? Interestingly,neuronal depolarization induced by NMDA and glutamatereceptors in the retina appears to regulate dendrite dynamicsthrough Rho and Rac (Wong et al., 2000). Studies in hippocampalneurons have identified the GEF Tiam1 as a crucial molecular linkbetween NMDA signaling and Rac1 (Tolias et al., 2005).Similarly, the GEF family of Ephexins regulates the activity ofRhoA, Rac and Cdc42 (Shamah et al., 2001; Sahin et al., 2005;Margolis et al., 2010). Interestingly, different Ephexin proteinsoperate downstream of distinct Eph receptors and have divergenteffects on Rho and Rac activation (Shamah et al., 2001; Margoliset al., 2010). For example, Ephexin5 (also known as Arhgef15)specifically stimulates RhoA activity with little or no effect on Racand Cdc42 (Margolis et al., 2010). Although Ephexins regulateaxon growth cone dynamics and synaptic development (Shamah etal., 2001; Sahin et al., 2005; Margolis et al., 2010), a function forEphexins, specifically Ephexin1, in dendrite morphogenesis hasbeen described (Wu et al., 2007). Beyond GEF-dependentactivation, Rac activity has also been linked to non-canonical Wntsignaling via catenins in hippocampal neurons (Yu and Malenka,2003; Rosso et al., 2005; Peng et al., 2009). This pathway isregulated by the postsynaptic protein Shank and the originrecognition core complex, both of which have functions indendrite morphogenesis (Huang et al., 2005; Quitsch et al., 2005).Together, these findings suggest that Rho family GTPases mightbe essential in transducing extracellular cues and other signals todirect structural changes within neurons.

Several studies have aimed to identify the key downstreameffectors of Rho family GTPases. RhoA activates the Rho-associatedkinase (ROK), and in hippocampal neurons ROK inhibitionsuppresses the reduction in dendrite length induced by constitutivelyactive RhoA expression (Nakayama et al., 2000), suggesting thatROK is required for RhoA function in dendrite morphogenesis.ROK, in turn, controls the phosphorylation of myosin light chainsand actomyosin contractility (Kimura et al., 1996; Hirose et al.,1998; Winter et al., 2001). Compared with RhoA, less is knownabout the downstream effectors of Rac1 and Cdc42 in the control ofdendrite morphogenesis. Rac1 and Cdc42 might converge on acommon signaling pathway. Consistent with this model, theserine/threonine kinase Pak1 appears to be activated by Rac1 andCdc42 and induces dendrite elaboration in immature corticalneurons (Hayashi et al., 2007). Rac1 and Cdc42 may also activatethe Arp2/3 complex (Chhabra and Higgs, 2007). However, furtherresearch is required to elucidate additional upstream regulators anddownstream effectors of Rho family GTPases.

Like Rho GTPases, the actin polymerization factor Enabled (Ena)appears to regulate the actin cytoskeleton to drive dendritepatterning. In Drosophila md sensory neurons, loss-of-functionmutations in ena cause dendrites to turn dorsally, and these dendrites

fail to reach segment boundaries (Gao et al., 1999). Interestingly,Ena and the tyrosine kinase Ableson (Abl) appear to act downstreamof the guidance receptor Roundabout (Robo) and the receptortyrosine phosphatase Dlar (also known as Lar) (Wills et al., 1999;Bashaw et al., 2000). Although Ena and its homologs form acomplex with actin cytoskeletal proteins and regulate actin dynamics(Lanier and Gertler, 2000), the specific molecular effectors of Enain dendrite morphogenesis remain to be elucidated.

Motor proteins and microtubule regulatorsFollowing extension of the actin cytoskeleton, dendrites must bestabilized by microtubules to maintain adequate structural integrity,a process that involves a number of microtubule motor and transportproteins. In contrast to those in axons, microtubules within dendritessupport transport in both directions (Baas et al., 1988; Baas et al.,1989). As demonstrated by depletion of the motor protein CHO1(also known as MKLP1 or KIF23) in sympathetic neurons, thesebidirectional microtubules are essential for the formation andmaintenance of dendrites (Sharp et al., 1997; Yu et al., 2000). Inaddition to CHO1, many other microtubule transport proteinscontribute to dendrite development. For example, in Drosophila,loss-of-function mutations in the genes encoding the minus-end-directed dynein motor protein Dhc64 and its associated proteinLissencephaly1 (Lis1) inhibit dendrite growth, branching, andmaturation in mushroom body neurons (Liu et al., 2000; Smith etal., 2000). Interestingly, LIS1 (also known as PAFAH1B1) mutationsin humans result in the loss of gyri and sulci, which leads to asmooth appearance of the cortex known as lissencephaly. Althoughthis pathology is primarily due to defects in the migration of corticalneurons, heterotropic pyramidal neurons of the hippocampus andearly cortical neurons in heterozygous Lis1 (Pafah1b1) mutant miceexhibit reduced dendrite length and branching (Fleck et al., 2000;Cahana et al., 2001). Additional motor proteins, including thekinesin family member Kif5, have been implicated in the traffickingof proteins required for dendrite growth (Hoogenraad et al., 2005).Other regulators appear to control the activity of motor proteins:Nna1 (also known as Agtpbp1), for example, regulates microtubulestability through intranuclear lysyl oxidase propeptide and NF-κBRelA signaling to direct Purkinje cell dendrite development (Li etal., 2010a). Collectively, these studies establish the important roleof microtubule motor proteins in the formation and maintenance ofdendrites.

Several molecules that link microtubule dynamics to the actincytoskeleton are also emerging as important regulators of dendritegrowth, supporting the idea that changes in the actin cytoskeletonof dendrites must subsequently be stabilized by microtubules. Forinstance, in the case of Lis1 and dynein, these proteins form acomplex with Nudel, which is a p35/Cdk5 substrate (p35 is aneuronal-specific activator of Cdk5) (Niethammer et al., 2000;Sasaki et al., 2000). Interestingly, p35/Cdk5 activity can beregulated by Rac (Nikolic et al., 1998), suggesting that p35/Cdk5might act as signaling link between the actin cytoskeleton andmicrotubules in neurons. In Drosophila, the large cytoskeletallinker protein Kakapo (Kak, also known as Short stop), which hasthe vertebrate homolog MACF, contains domains that bind to actinand microtubules (Gregory and Brown, 1998; Strumpf and Volk,1998). In kak mutant flies, microtubule structure is disrupted innumerous cell types, and, accordingly, dendrites in md neuronsand motoneurons exhibit defective branching (Prokop et al., 1998;Gao et al., 1999). Together, these studies suggest that linking actinand microtubule dynamics is crucial for the growth and branchingof dendrites.

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Trafficking and membrane remodeling during dendritemorphogenesis: a role for Golgi and endoplasmic reticulumproteinsThe growth and elaboration of dendrites requires large amounts ofplasma membrane and protein, demanding dedicated mechanismsfor polarized trafficking of cargo into new branches (Corty et al.,2009). Compartmentalized Golgi, known as Golgi outposts, areimportant components of the secretory pathway that are found ininvertebrate and mammalian dendrites (Horton and Ehlers, 2003;Horton et al., 2005; Ye et al., 2007). In rat hippocampal neurons,Golgi outposts tend to be found in longer, highly branched dendrites,and perturbations of Golgi trafficking in these neurons disruptsdendrite growth and maintenance (Horton et al., 2005; Pfenninger,2009). Moreover, local ablation of Golgi outposts reduces the branchdynamics of Drosophila da neurons (Ye et al., 2007). How mightGolgi outposts control dendrite morphogenesis? A recent studysuggests that Golgi outposts directly nucleate microtubules via theproteins γ-tubulin and CP309, a Drosophila homolog of themammalian centrosomal matrix protein AKAP450 (also known asAkap9) (Ori-McKenney et al., 2012). There are likely to beadditional mechanisms and functions downstream of Golgi outpoststhat remain to be defined.

Recent studies suggest that the dendritic endoplasmic reticulum(ER) might also play a role in the localization of essential proteinsat branch points, highlighting an important role for protein kinase C(PKC) and the ER protein CLIMP-63 (also known as Ckap4) inspatially limiting AMPA receptors in response to type I metabotropicglutamate receptor (mGluR) signaling (Cui-Wang et al., 2012).Remarkably, local zones of ER complexity reside at branch pointsthat work with these proteins to concentrate AMPA receptors. Thus,active mechanisms for localizing the secretory machinery, includingthe Golgi and ER, at sites of dendrite growth and remodeling mayregulate dendrite development.

In forward genetic screens in flies, several proteins that mediateER to Golgi transport, such as Dar2, Dar3 and Dar6, which areorthologs of the yeast proteins Sec23, Sar1 and Rab1, respectively,are required for dendrite elaboration in class IV da neurons (Ye etal., 2007). For example, Dar3 is necessary for vesicle formation asproteins traffic from the ER to the Golgi. Correspondingly, Dar3mutants have diffuse Golgi outposts and disrupted dendrite growth.Knockdown of the Dar3 homolog Sar1 in rat hippocampal neuronshas similar effects and specifically disrupts dendrite but not axondevelopment (Ye et al., 2007), suggesting that flies and mammalsuse evolutionarily conserved mechanisms to control dendriticsecretory trafficking.

How might Golgi proteins localize at sites of active dendriteremodeling? In Drosophila, the golgin coiled-coil adaptor proteinLava lamp (Lva) controls Golgi outpost distribution by associatingwith the microtubule-based motor complex dynein-dynactin.Consistent with this function, dominant-negative Lva causes Golgioutposts to shift to proximal dendrites, leading to a distal toproximal shift of dendrite branching in da neurons (Ye et al., 2007).Follow-up studies have found that additional mutations in dyneinlight intermediate chain 2 and dynein intermediate chain phenocopythe effect of lva mutations on Golgi outposts and dendritemorphogenesis (Satoh et al., 2008; Zheng et al., 2008). Because thedynein complex is a minus-end-directed motor, these findings raisethe intriguing possibility that dynein functions to traffic keycomponents of the branching machinery to expanding dendritearbors.

Key regulators of dendrite morphogenesis may act locally at theGolgi apparatus to control dendrite morphogenesis. Litterman et al.

have uncovered the E3 ubiquitin ligase Cul7-Fbxw8 as a crucialregulator of both Golgi morphogenesis and dendrite development(Litterman et al., 2011). Cul7-Fbxw8 localizes at the Golgiapparatus in neurons, and inhibition of Cul7-Fbxw8 impairs Golgimorphogenesis and function in granule neurons and consequentdendrite arbor elaboration in the rodent cerebellar cortex in vivo(Litterman et al., 2011). The cytoskeletal regulator Obsl1 interactswith Cul7-Fbxw8 and localizes Cul7 to the Golgi apparatus inneurons, and thus promotes dendrite growth (Litterman et al., 2011).Remarkably, mutations of CUL7 and OBSL1 cause the humandevelopmental disorder 3M syndrome (Huber et al., 2005;Maksimova et al., 2007; Hanson et al., 2009), raising the questionof whether dendrite abnormalities might occur in this disorder.Taken together, these findings suggest that protein complexes mightact locally at the Golgi apparatus to direct dendrite morphogenesis.

Along with the secretory pathway, the endocytic pathway mayregulate dendrite growth and branching by influencing the densityof cell surface receptors involved in dendrite morphogenesis (Janand Jan, 2010). For example, components of the early endocyticpathway, such as the small GTPase Rab5, facilitate arborization ofDrosophila da neurons in a dynein-dependent manner (Satoh et al.,2008). By contrast, mutations in the coiled-coil protein Shrub, theDrosophila homolog of yeast Snf7, which mediates endosome tolysosome trafficking via the ESCRT-III complex, cause exuberantbranching of dendrites in da neurons (Sweeney et al., 2006).Interestingly, in yeast, Snf7 is essential for the formation ofmultivesicular bodies (Teis et al., 2008; Saksena et al., 2009), raisingthe question of whether these endosomal compartments have a rolein dendrite patterning. What are the specific cell surface moleculesthat regulate dendrite morphogenesis? Recent data implicate theclathrin adaptor-associated kinase Nak in higher order dendritegrowth (Yang et al., 2011). Nak appears to interact with aspects ofthe endocytic pathway to direct the dendritic localization of clathrinpuncta at branch points and dendritic tips, where it facilitates theinternalization of the Drosophila L1CAM homolog Neuroglian. Inthe future, in addition to clarifying the endocytic machinery relevantto dendrite morphogenesis, it will be essential to identify additionalcargo of this pathway that directs dendrite development.

Factors that regulate dendritic field size and scalingIn order for information to be transmitted with high fidelity, dendritearbors must appropriately cover their target receptive fields ofinnervation. Dendrites must also grow to an appropriate size toavoid the overlap of processes from similar neuron types. As wediscuss below, Hippo family members and PI3K-mTor signalingproteins have emerged as important drivers of dendritic field sizeand the scaling of dendritic arbors.

Hippo family membersThe Ste20 family kinase Hippo regulates organ size in mammals andflies (Pan, 2007). In Drosophila, Hippo is positively regulated bySalvador (Sav) and phosphorylates and activates Warts (Wts), anuclear DBF2-related (NDR) kinase. In Drosophila da neurons, thiscomplex inhibits components of the polycomb repressor complex(PRC) to block transcriptional silencing (Parrish et al., 2007a).Consistent with this model, mutations in Hippo pathway membersor Polycomb group (PcG) genes impair dendrite maintenance inclass IV da neurons, leading to gaps in dendritic fields (Emoto et al.,2006; Parrish et al., 2007a), establishing a crucial role for Hippo-regulated Sav-Wts signaling in dendrite maintenance.

Hippo is also a key regulator of the NDR kinase Tricornered(Trc), which is activated by Furry (Fry). In Drosophila class IV da


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neurons, mutations in trc or fry were initially believed to renderdendrites insensitive to contact-mediated suppression of outgrowth,leading to overlapping dendritic fields and loss of dendritic tiling(Emoto et al., 2006). However, new analyses from Han et al.demonstrate that trc and fry mutants fail to confine dendrites in atwo-dimensional plane, allowing expansion of dendrites in threedimensions (Han et al., 2012). Consequently, dendrites in thesemutants are able to avoid contact-mediated repulsion, resulting inoverlapping receptive fields and the loss of tiling. Interestingly,components of TOR complex 2 (TORC2), including Sin1,Rapamycin-insensitive companion of Tor (Rictor) and Tor, form acomplex with Trc and trigger its activation and phosphorylation.Accordingly, mutations in these genes disrupt the tiling of class IVda neurons by failing to restrict dendrites to a two-dimensional plane(Koike-Kumagai et al., 2009; Han et al., 2012). Importantly, thesemechanisms appear to be evolutionary conserved: SAX-1 and SAX-2, the Caenorhabditis elegans homologs of Trc and Fry,respectively, also drive dendritic tiling. Together, these studiessuggest that Hippo signaling regulates Trc-Fry and Wts-Savsignaling to coordinate dendrite tiling and maintenance (Jan and Jan,2010).

In the mammalian brain, NDR kinases 1 and 2 (also known asStk38 and Stk38l) regulate dendrite arborization and dendritic spinedevelopment (Ultanir et al., 2012). Knockdown of NDR1/2 orexpression of dominant-negative NDR mutants increases dendritearborization and proximal branching in pyramidal neurons. AP2associated kinase (AAK1) and the GEF Rabin8 have been identifiedas substrates of NDR1/2 (Ultanir et al., 2012). Accordingly, theseintracellular vesicular trafficking proteins drive dendrite growth andspine development, respectively.

PI3K-mTOR signaling proteinsSeveral studies in both flies and mammals have suggested a functionfor phosphoinositide 3-kinase (PI3K) signaling in dendrite scalingand development. In flies, the PI3K-mammalian target of rapamycin(mTOR) pathway restricts dendrite development (Parrish et al.,2009); however, this pathway is regulated extrinsically byexpression of the microRNA bantam by neighboring epithelial cells,which in turn dampens Akt activity in the da neurons. In mammalianneurons, the PI3K-Akt-mTOR pathway promotes dendrite growth(Jaworski et al., 2005; Kumar et al., 2005). Additional studies usingneurons cultured from Reeler mice and wild-type littermates revealthat reelin stimulates mTOR-S6 kinase 1 signaling in a Dab1-dependent manner (Jossin and Goffinet, 2007). Strikingly,pharmacologic inhibition of PI3K, Akt or mTOR in hippocampalneurons blocks the stimulatory effects of reelin on dendrite growth(Jossin and Goffinet, 2007). Together, these findings suggest thatreelin operates upstream of PI3K and target of rapamycin complex1 and 2 (TORC1/2) signaling to regulate dendrite morphogenesis.Interestingly, mutations in components of target of TORC2,including Sin1, Rictor and Tor, have also been implicated in dendritepatterning in Drosophila. These TORC2 components form aphysical complex with Trc to drive class IV da neuron dendritictiling (Koike-Kumagai et al., 2009). Collectively, these studiessuggest that Ras-PI3K-mTOR as well as TORC2 signaling regulatedendrite development, with potential roles in dendrite scaling andtiling.

Cell cycle-regulated ubiquitin ligases and dendritedevelopmentA growing body of literature has identified novel functions for cellcycle proteins in postmitotic neurons (Kim and Bonni, 2007; Yang

et al., 2010; Puram and Bonni, 2011). Nearly a decade ago, themajor ubiquitin ligase Cdh1-APC was shown to restrict axongrowth in postmitotic neurons (Konishi et al., 2004), a finding thattriggered numerous analyses of the regulation and substrates ofthis protein complex (Huynh et al., 2009; Lasorella et al., 2006;Stegmuller et al., 2006). In light of Cdh1-APC function in axons,the role of the related ubiquitin ligase Cdc20-APC has been alsocharacterized in neurons (Kim et al., 2009; Puram et al., 2010).These studies revealed that components of the Cdc20-APCcomplex are expressed in the developing brain, where it promotesdendrite growth and elaboration (Kim et al., 2009). Thecentrosome-associated histone deacetylase 6 (Hdac6) promotes thepolyubiquitylation of Cdc20, thereby stimulating the ubiquitinligase activity of Cdc20-APC. In turn, centrosomal Cdc20-APCtriggers the polyubiquitylation and degradation of the HLH proteininhibitor of DNA binding 1 (Id1) to stimulate dendritedevelopment. Centrosomal Id1 controls dendrite development byinteracting with the ubiquitin receptor Rpn10 (also known as S5aor Psmd4) and thereby inhibiting proteasome activity at thecentrosome in neurons (Puram et al., 2013). The Cdc20-APC cell-intrinsic pathway of dendrite morphogenesis appears to beregulated upstream through cell-extrinsic cues such as calciumsignaling via the canonical calcium channel TRPC5 and the majorprotein kinase CaMKIIβ (Fig. 2) (Puram et al., 2011a; Puram etal., 2011b). In the future, it will be essential to determine whetheradditional regulators of centrosomal signaling can mediate theintegration of cell-extrinsic cues and cell-intrinsic signaling drivenby cell cycle proteins.

RNA targeting and local protein translation in dendritesIn order to rapidly extend and maintain dendrite branches, neuronsmust rapidly synthesize proteins locally within dendrites. Localtranslation appears to have a central role in dendrite morphogenesis(Chihara et al., 2007). The RNA-binding proteins Pumilio andNanos, which were originally identified as mRNA targeting proteinsin Drosophila embryos, are required for dendrite patterning in classIII and IV da neurons but not in class I and II neurons (Ye et al.,2004). In addition, following the period of initial dendrite growth,the maintenance and further branching of class IV da neurons inlarva depends on dendritic targeting of nanos mRNA along withGlorund and Smaug, which regulate nanos translation byrecognizing stem loops in its 3′ untranslated region (UTR)(Brechbiel and Gavis, 2008). Similarly, staufen 1 (Stau1), a double-stranded RNA-binding protein, has been linked to dendritic RNAlocalization in neurons, translational control and mRNA decay.Cultured hippocampal neurons from mutant mice with truncatedStau1 show defective dendritic targeting of Stau1 and β-actin (Actb)mRNA-containing ribonucleoproteins, and simplified dendriticarbors (Vessey et al., 2008). However, these animals have noobvious behavioral deficits, suggesting that Stau1 is likely to actredundantly with other local translation mechanisms. What mightlabel specific mRNAs for dendritic targeting? Buckley et al. haveidentified ID element retrotransposons, a retained class of shortinterspersed repetitive elements (SINEs), within the introns ofseveral dendritically targeted mRNAs (Buckley et al., 2011). Thesesequences are sufficient for targeting both endogenous andexogenous transcripts to dendrites, and, accordingly, appear toinfluence protein distribution within the cell. Thus, sequence-specific elements as well as RNA-protein interactions may directlocal dendritic translation.

In Xenopus, the mRNA-binding protein cytoplasmicpolyadenylation element binding protein 1 (CPEB1) regulates

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activity-dependent dendrite morphogenesis in the visual system.Using morpholino-mediated knockdown and mutant expressionstudies, Bestman and Cline proposed a role for CPEB1 in the localtranslation of mRNAs (Bestman and Cline, 2008). Consistent withthese findings, CaMKII phosphorylates CPEB in hippocampalneurons, which induces the interaction of CPEB with cytoplasmicpolyadenylation element (CPE)-like sequences in mRNA, thusstimulating translation (Atkins et al., 2004). A targeting function forCPEB has been proposed. Upon depolarization, CPEB is recruitedto CPE-like sequences in the 3′ UTR of BDNF mRNA, targeting themRNA to hippocampal neuron dendrites (Oe and Yoneda, 2010).Like CPEB1, Fragile X mental retardation protein (FMRP) regulatesthe trafficking and translation of mRNAs to the neuronal periphery,and thereby influences dendrite morphogenesis (Bagni and

Greenough, 2005). However, the precise mechanism by whichFMRP controls dendrite patterning remains unclear. These studiessuggest that mRNA-binding proteins such as CPEB1 and FMRP arecrucial regulators of mRNA targeting and translation in dendrites.Accordingly, defects in these cellular mechanisms may havedramatic consequences for the proper generation of neuronalcircuitry and brain function.

Conclusions and perspectivesRecent studies reveal an enormous degree of complexity in thesignaling mechanisms that control dendrite growth, patterning andmaintenance. Although numerous cell-intrinsic regulators, rangingfrom transcription factors to cytoskeletal proteins, orchestratedendrite morphogenesis (summarized in Fig. 3), there are several


Differentiationand patterningPruningGrowth and

branching

Hamlet (md)Cut, Knot and FascinSpineless (da)NeuroDCREBCREST

Rac1Cdc42Tiam1Pak1Arp2/3

CHO1Kif5Nna1Kak

Golgi outpostsDendritic ER – CLIMP63, PKCDar2, Dar3, Dar6Sar1Lava lampCul7-Fbxw8Rab5Nak

Hippo-Sav-WtsNDR1/2-AAK1 and Rab8mTor-S6 kinase 1-Dab1

HDAC6-Cdc20-APC-Id1-S5aTRPC5-CaMKIIβ-Cdc20-APCCul7-Fbxw8

miRNA bantum-PI3K-mTOR Tiling:Hippo-Trc-FryTORC2

Shrub

Hamlet (ES)AbruptSpineless (da)Sp4Ftzf1-EcrB1

RhoAEphexin5ROK

Cytoskeletal regulators

Transcriptional regulatorsand steroid hormones Differentiation:

MEF2A

Targeting:ACJ6 and DrifterLolaBap55-TIP60Rpd3-Prospero

Targeting:EnabledAbl

TF Targetgene

Other genes regulatingdendrites

Motor proteins

Secretory and endocytic pathways

Ubiquitin ligase pathways

Hippo pathway and PI3K signaling

Lis1

Dhc64Dhc64/Lis1Nudel

Cel

l-int

rinsi

c re

gula

tors

Centrosome

HDAC6 Id1

UbUb

Ub

Sav Hippo WtsP

TF

PRC

Targetgene

Cdc20

GTPRac1

Fig. 3. A summary of the key cell-intrinsic regulators of distinct stages of dendrite morphogenesis. Individual proteins or their signaling cassettesinvolved at each stage of dendrite morphogenesis are indicated, as described in the main text. In cases in which a given factor has opposing effects on twodifferent populations of neurons, the neuron type is listed in parentheses. D

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salient themes. It is clear that proteins involved in dendritemorphogenesis have functions that may be completely divergent orunrelated in non-neuronal cell types. The ubiquitin ligase Cdc20-APC is perhaps the quintessential example of this principle; Cdc20-APC drives dendrite growth and elaboration in neurons, but inmitotic cells is responsible for the transition from metaphase toanaphase (Kim et al., 2009; Puram et al., 2010). Thus, simplylimiting our analyses of dendrite morphogenesis to proteins knownto regulate morphology more generally is not sufficient. Forwardgenetic screens in Drosophila over the past 15 years havedemonstrated the utility of unbiased approaches in identifying noveldrivers of dendrite patterning (Scott and Luo, 2001; Jan and Jan,2003; Grueber and Jan, 2004; Parrish et al., 2006). In the future, itwill be useful to extend this approach to mammalian systems, whereRNAi libraries and similar approaches can be utilized tocomprehensively identify regulators of dendrite morphogenesis.Although implementation of such an approach will be challenginggiven the arduous methods for quantifying dendrite arbors,optimizing this hypothesis-generating approach will open up thepossibility of uncovering additional pathways that regulate dendritemorphogenesis in higher order vertebrates.

Regulators of dendrite patterning also appear to have dedicatedroles in driving specific phases of dendrite morphogenesis. Forexample, AMP-activated protein kinase (AMPK) phosphorylates themotor protein Kif5a to specify dendrites and establish their identityearly in morphogenesis (Parrish et al., 2006). Later in development,NeuroD stimulates early stages of dendrite growth and elaboration,while the transcription factors Sp4 and MEF2 trigger the pruningand maturation of dendrites, respectively (Gaudillière et al., 2004;Shalizi et al., 2006; Ramos et al., 2007). Together, our survey of theliterature reveals the emerging concept of specific cell-intrinsicregulators mapping onto distinct temporal phases of dendritedevelopment. Interestingly, several molecules, such as the NDRkinases, have roles in both dendrite morphogenesis and spineformation (Ultanir et al., 2012), raising the intriguing possibility thatthe same regulators of dendrite patterning have additional functionsin other phases of neuronal development. In the future, exploringcross-talk between signaling cascades that are active during distinctphases of development will be important in understanding thetransitions from one phase to another.

Although the diverse regulators of dendrite morphogenesis mustultimately converge on the dendrite itself, leading to changes suchas extension or retraction and branching or pruning, molecularintegration is likely to occur at earlier steps in signaling. Forexample, the cell-extrinsic regulators Wnt and Dishevelled (Dvl)modulate the activity of the Rho GTPase Rac and JNK, whereas thesecreted cue Sema3A triggers protein kinase A (PKA) activation,together providing a glimpse of how cell-extrinsic and cell-intrinsicregulators may ultimately be integrated. An important aspect of thefine-tuned control of dendrite morphogenesis appears to arise fromregulators working in synergy to offer homeostatic regulation. TheDrosophila transcription factors Cut, Knot and Spineless provide anelegant example of this combinatorial approach to signaling and itseffects on dendrite patterning. However, the opposing effects of Ftz-f1 and Hr39 on steroid hormone pathways or Rac1 and Cdc42 oncytoskeletal proteins demonstrate that this integrative approach isnot restricted to transcription factors. Rigorous investigation of thedownstream convergence of signaling pathways on individualdendrites offers a fruitful avenue for understanding the complexdynamics that mediate formation of the mature dendritic arbor.

Despite the extensive research into dendrite patterning during thepast two decades, new and exciting areas of general biology will

have a major impact on our understanding of dendritemorphogenesis in the years to come. For example, a recent study hasidentified a role for the microRNA bantam in repressing Akt activityand blocking the regeneration of dendrites in Drosophila da neurons(Ultanir et al., 2012). Similarly, the role of organelles such as theprimary cilium in dendrite morphogenesis remains to be elucidated.Defects in dendrite morphogenesis have been observed in neuronswith conditional deletion of cilia (Song et al., 2012), but theunderlying signaling mechanisms remain poorly characterized. Theauthors suggest that Wnt signaling might be dysregulated, therebymediating aberrations in dendrite patterning. There has also been anexplosion of interest in the secretory pathway and its functions indiverse aspects of biology, and the role of the secretory pathwaymachinery in dendrite morphogenesis is no exception (Kumamotoet al., 2012).

Characterizing the pathways regulating dendrite morphogenesisis likely to have profound consequences for our understanding ofdevelopmental disorders of cognition. Abnormalities in dendritemorphogenesis have been described in diverse neurologicaldisorders including autism spectrum disorders (ASD), Downsyndrome and Fragile X (Al-Bassam et al., 2012), as well asneurodegenerative disease (Takashima et al., 1981; Becker et al.,1986; Armstrong, 1995; Irwin et al., 2000; Kaufmann and Moser,2000; Dierssen and Ramakers, 2006; Pardo and Eberhart, 2007).Psychiatric disorders such as schizophrenia may also becharacterized by dendritic abnormalities (Graveland et al., 1985;Selkoe et al., 1987). In all these disorders, it remains unclearwhether dendrite defects represent the cause or effect of the disease;however, it is tempting to speculate that reversing dendriteabnormalities in these disorders might prove at least partiallyclinically beneficial. Although dendrite development is likely torequire a delicate balance between numerous molecular pathways,improving our understanding of these diverse regulators mightrender the manipulation of dendrite patterning a real possibility inthe future.

AcknowledgementsWe thank Luis Mejia, Luis de la Torre and other members of the A.B. laboratory forhelpful discussions and critical reading of the manuscript.

Competing interestsThe authors declare no competing financial interests.

FundingWork in the authors’ laboratories is supported by a grant from the NationalInstitutes of Health (NIH) to A.B. and from the NIH Medical Scientist TrainingProgram to S.V.P. Deposited in PMC for release after 12 months.

ReferencesAizawa, H., Hu, S. C., Bobb, K., Balakrishnan, K., Ince, G., Gurevich, I., Cowan, M.

and Ghosh, A. (2004). Dendrite development regulated by CREST, a calcium-regulated transcriptional activator. Science 303, 197-202.

Al-Bassam, S., Xu, M., Wandless, T. J. and Arnold, D. B. (2012). Differentialtrafficking of transport vesicles contributes to the localization of dendritic proteins.Cell Rep. 2, 89-100.

Amthor, F. R. and Oyster, C. W. (1995). Spatial organization of retinal informationabout the direction of image motion. Proc. Natl. Acad. Sci. USA 92, 4002-4005.

Armstrong, D. D. (1995). The neuropathology of Rett syndrome—overview 1994.Neuropediatrics 26, 100-104.

Arnold, D., Feng, L., Kim, J. and Heintz, N. (1994). A strategy for the analysis ofgene expression during neural development. Proc. Natl. Acad. Sci. USA 91, 9970-9974.

Atkins, C. M., Nozaki, N., Shigeri, Y. and Soderling, T. R. (2004). Cytoplasmicpolyadenylation element binding protein-dependent protein synthesis is regulated bycalcium/calmodulin-dependent protein kinase II. J. Neurosci. 24, 5193-5201.

Baas, P. W. and Lin, S. (2011). Hooks and comets: The story of microtubule polarityorientation in the neuron. Dev. Neurobiol. 71, 403-418.

Baas, P. W., Deitch, J. S., Black, M. M. and Banker, G. A. (1988). Polarity orientationof microtubules in hippocampal neurons: uniformity in the axon and nonuniformity inthe dendrite. Proc. Natl. Acad. Sci. USA 85, 8335-8339.

4667


DEVELO

PMENT

4668

Baas, P. W., Black, M. M. and Banker, G. A. (1989). Changes in microtubule polarityorientation during the development of hippocampal neurons in culture. J. Cell Biol.109, 3085-3094.

Baas, P. W., Slaughter, T., Brown, A. and Black, M. M. (1991). Microtubule dynamicsin axons and dendrites. J. Neurosci. Res. 30, 134-153.

Bagni, C. and Greenough, W. T. (2005). From mRNP trafficking to spinedysmorphogenesis: the roots of fragile X syndrome. Nat. Rev. Neurosci. 6, 376-387.

Barnes, A. P. and Polleux, F. (2009). Establishment of axon-dendrite polarity indeveloping neurons. Annu. Rev. Neurosci. 32, 347-381.

Bashaw, G. J., Kidd, T., Murray, D., Pawson, T. and Goodman, C. S. (2000).Repulsive axon guidance: Abelson and Enabled play opposing roles downstream ofthe roundabout receptor. Cell 101, 703-715.

Becker, L. E., Armstrong, D. L. and Chan, F. (1986). Dendritic atrophy in childrenwith Down’s syndrome. Ann. Neurol. 20, 520-526.

Bestman, J. E. and Cline, H. T. (2008). The RNA binding protein CPEB regulatesdendrite morphogenesis and neuronal circuit assembly in vivo. Proc. Natl. Acad. Sci.USA 105, 20494-20499.

Blochlinger, K., Bodmer, R., Jan, L. Y. and Jan, Y. N. (1990). Patterns of expressionof cut, a protein required for external sensory organ development in wild-type andcut mutant Drosophila embryos. Genes Dev. 4, 1322-1331.

Bokoch, G. M. (2003). Biology of the p21-activated kinases. Annu. Rev. Biochem. 72,743-781.

Boulanger, A., Clouet-Redt, C., Farge, M., Flandre, A., Guignard, T., Fernando, C.,Juge, F. and Dura, J. M. (2011). ftz-f1 and Hr39 opposing roles on EcR expressionduring Drosophila mushroom body neuron remodeling. Nat. Neurosci. 14, 37-44.

Branco, T. and Häusser, M. (2011). Synaptic integration gradients in single corticalpyramidal cell dendrites. Neuron 69, 885-892.

Branco, T., Clark, B. A. and Häusser, M. (2010). Dendritic discrimination of temporalinput sequences in cortical neurons. Science 329, 1671-1675.

Brechbiel, J. L. and Gavis, E. R. (2008). Spatial regulation of nanos is required for itsfunction in dendrite morphogenesis. Curr. Biol. 18, 745-750.

Buckley, P. T., Lee, M. T., Sul, J. Y., Miyashiro, K. Y., Bell, T. J., Fisher, S. A., Kim,J. and Eberwine, J. (2011). Cytoplasmic intron sequence-retaining transcripts canbe dendritically targeted via ID element retrotransposons. Neuron 69, 877-884.

Cáceres, A., Ye, B. and Dotti, C. G. (2012). Neuronal polarity: demarcation, growthand commitment. Curr. Opin. Cell Biol. 24, 547-553.

Cahana, A., Escamez, T., Nowakowski, R. S., Hayes, N. L., Giacobini, M., vonHolst, A., Shmueli, O., Sapir, T., McConnell, S. K., Wurst, W. et al. (2001).Targeted mutagenesis of Lis1 disrupts cortical development and LIS1homodimerization. Proc. Natl. Acad. Sci. USA 98, 6429-6434.

Causeret, F., Terao, M., Jacobs, T., Nishimura, Y. V., Yanagawa, Y., Obata, K.,Hoshino, M. and Nikolic, M. (2009). The p21-activated kinase is required forneuronal migration in the cerebral cortex. Cereb. Cortex 19, 861-875.

Chen, H. and Firestein, B. L. (2007). RhoA regulates dendrite branching inhippocampal neurons by decreasing cypin protein levels. J. Neurosci. 27, 8378-8386.

Chen, Y., Wang, P. Y. and Ghosh, A. (2005). Regulation of cortical dendritedevelopment by Rap1 signaling. Mol. Cell. Neurosci. 28, 215-228.

Chhabra, E. S. and Higgs, H. N. (2007). The many faces of actin: matching assemblyfactors with cellular structures. Nat. Cell Biol. 9, 1110-1121.

Chihara, T., Luginbuhl, D. and Luo, L. (2007). Cytoplasmic and mitochondrial proteintranslation in axonal and dendritic terminal arborization. Nat. Neurosci. 10, 828-837.

Christensen, R., de la Torre-Ubieta, L., Bonni, A. and Colón-Ramos, D. A. (2011).A conserved PTEN/FOXO pathway regulates neuronal morphology during C.elegans development. Development 138, 5257-5267.

Corty, M. M., Matthews, B. J. and Grueber, W. B. (2009). Molecules andmechanisms of dendrite development in Drosophila. Development 136, 1049-1061.

Craig, A. M. and Banker, G. (1994). Neuronal polarity. Annu. Rev. Neurosci. 17, 267-310.

Crozatier, M. and Vincent, A. (2008). Control of multidendritic neuron differentiation inDrosophila: the role of Collier. Dev. Biol. 315, 232-242.

Cubelos, B., Sebastián-Serrano, A., Beccari, L., Calcagnotto, M. E., Cisneros, E.,Kim, S., Dopazo, A., Alvarez-Dolado, M., Redondo, J. M., Bovolenta, P. et al.(2010). Cux1 and Cux2 regulate dendritic branching, spine morphology, andsynapses of the upper layer neurons of the cortex. Neuron 66, 523-535.

Cui-Wang, T., Hanus, C., Cui, T., Helton, T., Bourne, J., Watson, D., Harris, K. M.and Ehlers, M. D. (2012). Local zones of endoplasmic reticulum complexity confinecargo in neuronal dendrites. Cell 148, 309-321.

Dailey, M. E. and Smith, S. J. (1996). The dynamics of dendritic structure indeveloping hippocampal slices. J. Neurosci. 16, 2983-2994.

de la Torre-Ubieta, L. and Bonni, A. (2011). Transcriptional regulation of neuronalpolarity and morphogenesis in the mammalian brain. Neuron 72, 22-40.

de la Torre-Ubieta, L., Gaudillière, B., Yang, Y., Ikeuchi, Y., Yamada, T., DiBacco,S., Stegmüller, J., Schüller, U., Salih, D. A., Rowitch, D. et al. (2010). A FOXO-Pak1 transcriptional pathway controls neuronal polarity. Genes Dev. 24, 799-813.

Dierssen, M. and Ramakers, G. J. (2006). Dendritic pathology in mental retardation:from molecular genetics to neurobiology. Genes Brain Behav. 5 Suppl., 48-60.

Dijkhuizen, P. A. and Ghosh, A. (2005). Regulation of dendritic growth by calciumand neurotrophin signaling. Prog. Brain Res. 147, 15-27.

Emoto, K., Parrish, J. Z., Jan, L. Y. and Jan, Y. N. (2006). The tumour suppressorHippo acts with the NDR kinases in dendritic tiling and maintenance. Nature 443,210-213.

Flavell, S. W., Cowan, C. W., Kim, T. K., Greer, P. L., Lin, Y., Paradis, S., Griffith, E.C., Hu, L. S., Chen, C. and Greenberg, M. E. (2006). Activity-dependent regulation

of MEF2 transcription factors suppresses excitatory synapse number. Science 311,1008-1012.

Fleck, M. W., Hirotsune, S., Gambello, M. J., Phillips-Tansey, E., Suares, G.,Mervis, R. F., Wynshaw-Boris, A. and McBain, C. J. (2000). Hippocampalabnormalities and enhanced excitability in a murine model of human lissencephaly.J. Neurosci. 20, 2439-2450.

Gan, W. B., Grutzendler, J., Wong, W. T., Wong, R. O. and Lichtman, J. W. (2000).Multicolor “DiOlistic” labeling of the nervous system using lipophilic dyecombinations. Neuron 27, 219-225.

Gao, F. B., Brenman, J. E., Jan, L. Y. and Jan, Y. N. (1999). Genes regulatingdendritic outgrowth, branching, and routing in Drosophila. Genes Dev. 13, 2549-2561.

Gao, Z., Ure, K., Ables, J. L., Lagace, D. C., Nave, K. A., Goebbels, S., Eisch, A. J.and Hsieh, J. (2009). Neurod1 is essential for the survival and maturation of adult-born neurons. Nat. Neurosci. 12, 1090-1092.

Gaudillière, B., Konishi, Y., de la Iglesia, N., Yao, G. and Bonni, A. (2004). ACaMKII-NeuroD signaling pathway specifies dendritic morphogenesis. Neuron 41,229-241.

Gidon, A. and Segev, I. (2012). Principles governing the operation of synapticinhibition in dendrites. Neuron 75, 330-341.

Goldberg, J. L. (2004). Intrinsic neuronal regulation of axon and dendrite growth. Curr.Opin. Neurobiol. 14, 551-557.

Goldberg, J. L., Klassen, M. P., Hua, Y. and Barres, B. A. (2002). Amacrine-signaledloss of intrinsic axon growth ability by retinal ganglion cells. Science 296, 1860-1864.

Graveland, G. A., Williams, R. S. and DiFiglia, M. (1985). Evidence for degenerativeand regenerative changes in neostriatal spiny neurons in Huntington’s disease.Science 227, 770-773.

Gregory, S. L. and Brown, N. H. (1998). kakapo, a gene required for adhesionbetween and within cell layers in Drosophila, encodes a large cytoskeletal linkerprotein related to plectin and dystrophin. J. Cell Biol. 143, 1271-1282.

Grueber, W. B. and Jan, Y. N. (2004). Dendritic development: lessons from Drosophilaand related branches. Curr. Opin. Neurobiol. 14, 74-82.

Grueber, W. B., Jan, L. Y. and Jan, Y. N. (2002). Tiling of the Drosophila epidermis bymultidendritic sensory neurons. Development 129, 2867-2878.

Grueber, W. B., Jan, L. Y. and Jan, Y. N. (2003). Different levels of the homeodomainprotein cut regulate distinct dendrite branching patterns of Drosophila multidendriticneurons. Cell 112, 805-818.

Hahn, M. E. (2002). Aryl hydrocarbon receptors: diversity and evolution. Chem. Biol.Interact. 141, 131-160.

Hámori, J. and Somogyi, J. (1983). Differentiation of cerebellar mossy fiber synapsesin the rat: a quantitative electron microscope study. J. Comp. Neurol. 220, 365-377.

Han, C., Wang, D., Soba, P., Zhu, S., Lin, X., Jan, L. Y. and Jan, Y. N. (2012).Integrins regulate repulsion-mediated dendritic patterning of drosophila sensoryneurons by restricting dendrites in a 2D space. Neuron 73, 64-78.

Hand, R., Bortone, D., Mattar, P., Nguyen, L., Heng, J. I., Guerrier, S., Boutt, E.,Peters, E., Barnes, A. P., Parras, C. et al. (2005). Phosphorylation of Neurogenin2specifies the migration properties and the dendritic morphology of pyramidal neuronsin the neocortex. Neuron 48, 45-62.

Hanson, D., Murray, P. G., Sud, A., Temtamy, S. A., Aglan, M., Superti-Furga, A.,Holder, S. E., Urquhart, J., Hilton, E., Manson, F. D. et al. (2009). The primordialgrowth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptorOBSL1. Am. J. Hum. Genet. 84, 801-806.

Hattori, Y., Sugimura, K. and Uemura, T. (2007). Selective expression of Knot/Collier,a transcriptional regulator of the EBF/Olf-1 family, endows the Drosophila sensorysystem with neuronal class-specific elaborated dendritic patterns. Genes Cells 12,1011-1022.

Häusser, M., Spruston, N. and Stuart, G. J. (2000). Diversity and dynamics ofdendritic signaling. Science 290, 739-744.

Hayashi, K., Ohshima, T., Hashimoto, M. and Mikoshiba, K. (2007). Pak1 regulatesdendritic branching and spine formation. Dev. Neurobiol. 67, 655-669.

Hirose, M., Ishizaki, T., Watanabe, N., Uehata, M., Kranenburg, O., Moolenaar, W.H., Matsumura, F., Maekawa, M., Bito, H. and Narumiya, S. (1998). Moleculardissection of the Rho-associated protein kinase (p160ROCK)-regulated neuriteremodeling in neuroblastoma N1E-115 cells. J. Cell Biol. 141, 1625-1636.

Holtmaat, A., Bonhoeffer, T., Chow, D. K., Chuckowree, J., De Paola, V., Hofer, S.B., Hübener, M., Keck, T., Knott, G., Lee, W. C. et al. (2009). Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window. Nat.Protoc. 4, 1128-1144.

Hoogenraad, C. C., Milstein, A. D., Ethell, I. M., Henkemeyer, M. and Sheng, M.(2005). GRIP1 controls dendrite morphogenesis by regulating EphB receptortrafficking. Nat. Neurosci. 8, 906-915.

Horch, H. W., Krüttgen, A., Portbury, S. D. and Katz, L. C. (1999). Destabilization ofcortical dendrites and spines by BDNF. Neuron 23, 353-364.

Horton, A. C. and Ehlers, M. D. (2003). Dual modes of endoplasmic reticulum-to-Golgi transport in dendrites revealed by live-cell imaging. J. Neurosci. 23, 6188-6199.

Horton, A. C., Rácz, B., Monson, E. E., Lin, A. L., Weinberg, R. J. and Ehlers, M. D.(2005). Polarized secretory trafficking directs cargo for asymmetric dendrite growthand morphogenesis. Neuron 48, 757-771.

Huang, Z., Zang, K. and Reichardt, L. F. (2005). The origin recognition core complexregulates dendrite and spine development in postmitotic neurons. J. Cell Biol. 170,527-535.

Huber, C., Dias-Santagata, D., Glaser, A., O’Sullivan, J., Brauner, R., Wu, K., Xu,X., Pearce, K., Wang, R., Uzielli, M. L. et al. (2005). Identification of mutations inCUL7 in 3-M syndrome. Nat. Genet. 37, 1119-1124.


DEVELO

PMENT

Huckfeldt, R. M., Schubert, T., Morgan, J. L., Godinho, L., Di Cristo, G., Huang, Z.J. and Wong, R. O. (2009). Transient neurites of retinal horizontal cells exhibitcolumnar tiling via homotypic interactions. Nat. Neurosci. 12, 35-43.

Huynh, M. A., Stegmüller, J., Litterman, N. and Bonni, A. (2009). Regulation ofCdh1-APC function in axon growth by Cdh1 phosphorylation. J. Neurosci. 29, 4322-4327.

Huynh, M. A., Ikeuchi, Y., Netherton, S., de la Torre-Ubieta, L., Kanadia, R.,Stegmüller, J., Cepko, C., Bonni, S. and Bonni, A. (2011). An isoform-specificSnoN1-FOXO1 repressor complex controls neuronal morphogenesis and positioningin the mammalian brain. Neuron 69, 930-944.

Irwin, S. A., Galvez, R. and Greenough, W. T. (2000). Dendritic spine structuralanomalies in fragile-X mental retardation syndrome. Cereb. Cortex 10, 1038-1044.

Jacobs, T., Causeret, F., Nishimura, Y. V., Terao, M., Norman, A., Hoshino, M. andNikolić, M. (2007). Localized activation of p21-activated kinase controls neuronalpolarity and morphology. J. Neurosci. 27, 8604-8615.

Jan, Y. N. and Jan, L. Y. (2003). The control of dendrite development. Neuron 40, 229-242.

Jan, Y. N. and Jan, L. Y. (2010). Branching out: mechanisms of dendritic arborization.Nat. Rev. Neurosci. 11, 316-328.

Jaworski, J., Spangler, S., Seeburg, D. P., Hoogenraad, C. C. and Sheng, M.(2005). Control of dendritic arborization by the phosphoinositide-3′-kinase-Akt-mammalian target of rapamycin pathway. J. Neurosci. 25, 11300-11312.

Jinushi-Nakao, S., Arvind, R., Amikura, R., Kinameri, E., Liu, A. W. and Moore, A.W. (2007). Knot/Collier and cut control different aspects of dendrite cytoskeleton andsynergize to define final arbor shape. Neuron 56, 963-978.

Jossin, Y. and Goffinet, A. M. (2007). Reelin signals through phosphatidylinositol 3-kinase and Akt to control cortical development and through mTor to regulatedendritic growth. Mol. Cell. Biol. 27, 7113-7124.

Karlsgodt, K. H., Sun, D., Jimenez, A. M., Lutkenhoff, E. S., Willhite, R., van Erp, T.G. and Cannon, T. D. (2008). Developmental disruptions in neural connectivity inthe pathophysiology of schizophrenia. Dev. Psychopathol. 20, 1297-1327.

Kaufmann, W. E. and Moser, H. W. (2000). Dendritic anomalies in disordersassociated with mental retardation. Cereb. Cortex 10, 981-991.

Kim, A. H. and Bonni, A. (2007). Thinking within the D box: initial identification ofCdh1-APC substrates in the nervous system. Mol. Cell. Neurosci. 34, 281-287.

Kim, S. and Chiba, A. (2004). Dendritic guidance. Trends Neurosci. 27, 194-202. Kim, M. D., Jan, L. Y. and Jan, Y. N. (2006). The bHLH-PAS protein Spineless is

necessary for the diversification of dendrite morphology of Drosophila dendriticarborization neurons. Genes Dev. 20, 2806-2819.

Kim, A. H., Puram, S. V., Bilimoria, P. M., Ikeuchi, Y., Keough, S., Wong, M.,Rowitch, D. and Bonni, A. (2009). A centrosomal Cdc20-APC pathway controlsdendrite morphogenesis in postmitotic neurons. Cell 136, 322-336.

Kimura, K., Ito, M., Amano, M., Chihara, K., Fukata, Y., Nakafuku, M., Yamamori,B., Feng, J., Nakano, T., Okawa, K. et al. (1996). Regulation of myosinphosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273, 245-248.

Kirilly, D., Wong, J. J., Lim, E. K., Wang, Y., Zhang, H., Wang, C., Liao, Q., Wang,H., Liou, Y. C., Wang, H. et al. (2011). Intrinsic epigenetic factors cooperate with thesteroid hormone ecdysone to govern dendrite pruning in Drosophila. Neuron 72, 86-100.

Koike-Kumagai, M., Yasunaga, K., Morikawa, R., Kanamori, T. and Emoto, K.(2009). The target of rapamycin complex 2 controls dendritic tiling of Drosophilasensory neurons through the Tricornered kinase signalling pathway. EMBO J. 28,3879-3892.

Komiyama, T. and Luo, L. (2007). Intrinsic control of precise dendritic targeting by anensemble of transcription factors. Curr. Biol. 17, 278-285.

Komiyama, T., Johnson, W. A., Luo, L. and Jefferis, G. S. (2003). From lineage towiring specificity. POU domain transcription factors control precise connections ofDrosophila olfactory projection neurons. Cell 112, 157-167.

Konishi, Y., Stegmüller, J., Matsuda, T., Bonni, S. and Bonni, A. (2004). Cdh1-APCcontrols axonal growth and patterning in the mammalian brain. Science 303, 1026-1030.

Konur, S. and Ghosh, A. (2005). Calcium signaling and the control of dendriticdevelopment. Neuron 46, 401-405.

Kramer, A. P. and Kuwada, J. Y. (1983). Formation of the receptive fields of leechmechanosensory neurons during embryonic development. J. Neurosci. 3, 2474-2486.

Kumamoto, N., Gu, Y., Wang, J., Janoschka, S., Takemaru, K., Levine, J. and Ge,S. (2012). A role for primary cilia in glutamatergic synaptic integration of adult-bornneurons. Nat. Neurosci. 15, 399-405, S1.

Kumar, V., Zhang, M. X., Swank, M. W., Kunz, J. and Wu, G. Y. (2005). Regulation ofdendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signalingpathways. J. Neurosci. 25, 11288-11299.

Landgraf, M., Jeffrey, V., Fujioka, M., Jaynes, J. B. and Bate, M. (2003). Embryonicorigins of a motor system: motor dendrites form a myotopic map in Drosophila. PLoSBiol. 1, E41.

Lanier, L. M. and Gertler, F. B. (2000). From Abl to actin: Abl tyrosine kinase andassociated proteins in growth cone motility. Curr. Opin. Neurobiol. 10, 80-87.

Lasorella, A., Stegmüller, J., Guardavaccaro, D., Liu, G., Carro, M. S., Rothschild,G., de la Torre-Ubieta, L., Pagano, M., Bonni, A. and Iavarone, A. (2006).Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit andaxonal growth. Nature 442, 471-474.

Lavzin, M., Rapoport, S., Polsky, A., Garion, L. and Schiller, J. (2012). Nonlineardendritic processing determines angular tuning of barrel cortex neurons in vivo.Nature 490, 397-401.

Lee, T. and Luo, L. (1999). Mosaic analysis with a repressible cell marker for studiesof gene function in neuronal morphogenesis. Neuron 22, 451-461.

Lee, T., Winter, C., Marticke, S. S., Lee, A. and Luo, L. (2000). Essential roles ofDrosophila RhoA in the regulation of neuroblast proliferation and dendritic but notaxonal morphogenesis. Neuron 25, 307-316.

Lee, A., Li, W., Xu, K., Bogert, B. A., Su, K. and Gao, F. B. (2003). Control ofdendritic development by the Drosophila fragile X-related gene involves the smallGTPase Rac1. Development 130, 5543-5552.

Leemhuis, J., Boutillier, S., Barth, H., Feuerstein, T. J., Brock, C., Nürnberg, B.,Aktories, K. and Meyer, D. K. (2004). Rho GTPases and phosphoinositide 3-kinaseorganize formation of branched dendrites. J. Biol. Chem. 279, 585-596.

Li, W. and Gao, F. B. (2003). Actin filament-stabilizing protein tropomyosin regulatesthe size of dendritic fields. J. Neurosci. 23, 6171-6175.

Li, Z., Van Aelst, L. and Cline, H. T. (2000). Rho GTPases regulate distinct aspects ofdendritic arbor growth in Xenopus central neurons in vivo. Nat. Neurosci. 3, 217-225.

Li, W., Wang, F., Menut, L. and Gao, F. B. (2004). BTB/POZ-zinc finger protein abruptsuppresses dendritic branching in a neuronal subtype-specific and dosage-dependent manner. Neuron 43, 823-834.

Li, J., Gu, X., Ma, Y., Calicchio, M. L., Kong, D., Teng, Y. D., Yu, L., Crain, A. M.,Vartanian, T. K., Pasqualini, R. et al. (2010a). Nna1 mediates Purkinje cell dendriticdevelopment via lysyl oxidase propeptide and NF-κB signaling. Neuron 68, 45-60.

Li, N., Zhao, C. T., Wang, Y. and Yuan, X. B. (2010b). The transcription factor Cux1regulates dendritic morphology of cortical pyramidal neurons. PLoS ONE 5, e10596.

Litterman, N., Ikeuchi, Y., Gallardo, G., O’Connell, B. C., Sowa, M. E., Gygi, S. P.,Harper, J. W. and Bonni, A. (2011). An OBSL1-Cul7Fbxw8 ubiquitin ligasesignaling mechanism regulates Golgi morphology and dendrite patterning. PLoSBiol. 9, e1001060.

Liu, Z., Steward, R. and Luo, L. (2000). Drosophila Lis1 is required for neuroblastproliferation, dendritic elaboration and axonal transport. Nat. Cell Biol. 2, 776-783.

Lo, D. C., McAllister, A. K. and Katz, L. C. (1994). Neuronal transfection in brainslices using particle-mediated gene transfer. Neuron 13, 1263-1268.

Maksimova, N., Hara, K., Miyashia, A., Nikolaeva, I., Shiga, A., Nogovicina, A.,Sukhomyasova, A., Argunov, V., Shvedova, A., Ikeuchi, T. et al. (2007). Clinical,molecular and histopathological features of short stature syndrome with novel CUL7mutation in Yakuts: new population isolate in Asia. J. Med. Genet. 44, 772-778.

Margolis, S. S., Salogiannis, J., Lipton, D. M., Mandel-Brehm, C., Wills, Z. P.,Mardinly, A. R., Hu, L., Greer, P. L., Bikoff, J. B., Ho, H. Y. et al. (2010). EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake onexcitatory synapse formation. Cell 143, 442-455.

McAllister, A. K., Lo, D. C. and Katz, L. C. (1995). Neurotrophins regulate dendriticgrowth in developing visual cortex. Neuron 15, 791-803.

McAllister, A. K., Katz, L. C. and Lo, D. C. (1996). Neurotrophin regulation of corticaldendritic growth requires activity. Neuron 17, 1057-1064.

Mertz, K., Koscheck, T. and Schilling, K. (2000). Brain-derived neurotrophic factormodulates dendritic morphology of cerebellar basket and stellate cells: an in vitrostudy. Neuroscience 97, 303-310.

Millard, S. S. and Zipursky, S. L. (2008). Dscam-mediated repulsion controls tilingand self-avoidance. Curr. Opin. Neurobiol. 18, 84-89.

Miller, F. D. and Kaplan, D. R. (2003). Signaling mechanisms underlying dendriteformation. Curr. Opin. Neurobiol. 13, 391-398.

Mohideen, F., Capili, A. D., Bilimoria, P. M., Yamada, T., Bonni, A. and Lima, C. D.(2009). A molecular basis for phosphorylation-dependent SUMO conjugation by theE2 UBC9. Nat. Struct. Mol. Biol. 16, 945-952.

Moore, A. W., Jan, L. Y. and Jan, Y. N. (2002). hamlet, a binary genetic switchbetween single- and multiple- dendrite neuron morphology. Science 297, 1355-1358.

Nagel, J., Delandre, C., Zhang, Y., Förstner, F., Moore, A. W. and Tavosanis, G.(2012). Fascin controls neuronal class-specific dendrite arbor morphology.Development 139, 2999-3009.

Nakayama, A. Y., Harms, M. B. and Luo, L. (2000). Small GTPases Rac and Rho inthe maintenance of dendritic spines and branches in hippocampal pyramidalneurons. J. Neurosci. 20, 5329-5338.

Nedivi, E., Wu, G. Y. and Cline, H. T. (1998). Promotion of dendritic growth byCPG15, an activity-induced signaling molecule. Science 281, 1863-1866.

Newey, S. E., Velamoor, V., Govek, E. E. and Van Aelst, L. (2005). Rho GTPases,dendritic structure, and mental retardation. J. Neurobiol. 64, 58-74.

Ng, J., Nardine, T., Harms, M., Tzu, J., Goldstein, A., Sun, Y., Dietzl, G., Dickson,B. J. and Luo, L. (2002). Rac GTPases control axon growth, guidance andbranching. Nature 416, 442-447.

Niethammer, M., Smith, D. S., Ayala, R., Peng, J., Ko, J., Lee, M. S., Morabito, M.and Tsai, L. H. (2000). NUDEL is a novel Cdk5 substrate that associates with LIS1and cytoplasmic dynein. Neuron 28, 697-711.

Nikolic, M., Chou, M. M., Lu, W., Mayer, B. J. and Tsai, L. H. (1998). The p35/Cdk5kinase is a neuron-specific Rac effector that inhibits Pak1 activity. Nature 395, 194-198.

Oe, S. and Yoneda, Y. (2010). Cytoplasmic polyadenylation element-like sequencesare involved in dendritic targeting of BDNF mRNA in hippocampal neurons. FEBSLett. 584, 3424-3430.

Okazawa, M., Abe, H., Katsukawa, M., Iijima, K., Kiwada, T. and Nakanishi, S.(2009). Role of calcineurin signaling in membrane potential-regulated maturation ofcerebellar granule cells. J. Neurosci. 29, 2938-2947.

Ori-McKenney, K. M., Jan, L. Y. and Jan, Y. N. (2012). Golgi outposts shape dendritemorphology by functioning as sites of acentrosomal microtubule nucleation inneurons. Neuron 76, 921-930.

Palay, S. and Chan-Palay, V. (1974). Cerebellar Cortex: Cytology and Organization.New York, NY: Springer-Verlag.

4669


DEVELO

PMENT

4670

Pan, D. (2007). Hippo signaling in organ size control. Genes Dev. 21, 886-897. Pardo, C. A. and Eberhart, C. G. (2007). The neurobiology of autism. Brain Pathol.

17, 434-447. Parrish, J. Z., Kim, M. D., Jan, L. Y. and Jan, Y. N. (2006). Genome-wide analyses

identify transcription factors required for proper morphogenesis of Drosophilasensory neuron dendrites. Genes Dev. 20, 820-835.

Parrish, J. Z., Emoto, K., Jan, L. Y. and Jan, Y. N. (2007a). Polycomb genes interactwith the tumor suppressor genes hippo and warts in the maintenance of Drosophilasensory neuron dendrites. Genes Dev. 21, 956-972.

Parrish, J. Z., Emoto, K., Kim, M. D. and Jan, Y. N. (2007b). Mechanisms thatregulate establishment, maintenance, and remodeling of dendritic fields. Annu. Rev.Neurosci. 30, 399-423.

Parrish, J. Z., Xu, P., Kim, C. C., Jan, L. Y. and Jan, Y. N. (2009). The microRNAbantam functions in epithelial cells to regulate scaling growth of dendrite arbors indrosophila sensory neurons. Neuron 63, 788-802.

Peng, Y. R., He, S., Marie, H., Zeng, S. Y., Ma, J., Tan, Z. J., Lee, S. Y., Malenka, R.C. and Yu, X. (2009). Coordinated changes in dendritic arborization and synapticstrength during neural circuit development. Neuron 61, 71-84.

Perry, V. H. and Linden, R. (1982). Evidence for dendritic competition in thedeveloping retina. Nature 297, 683-685.

Peters, A., Palay, S. L. and Webster, H. D. (1991). The Fine Structure of the NervousSystem: Neurons and Their Supporting Cells. New York, NY: Oxford UniversityPress.

Pfenninger, K. H. (2009). Plasma membrane expansion: a neuron’s Herculean task.Nat. Rev. Neurosci. 10, 251-261.

Prokop, A., Uhler, J., Roote, J. and Bate, M. (1998). The kakapo mutation affectsterminal arborization and central dendritic sprouting of Drosophila motorneurons. J.Cell Biol. 143, 1283-1294.

Puram, S. V. and Bonni, A. (2011). Novel functions for the anaphase-promotingcomplex in neurobiology. Semin. Cell Dev. Biol. 22, 586-594.

Puram, S. V., Kim, A. H. and Bonni, A. (2010). An old dog learns new tricks: a novelfunction for Cdc20-APC in dendrite morphogenesis in neurons. Cell Cycle 9, 482-485.

Puram, S. V., Kim, A. H., Ikeuchi, Y., Wilson-Grady, J. T., Merdes, A., Gygi, S. P.and Bonni, A. (2011a). A CaMKIIβ signaling pathway at the centrosome regulatesdendrite patterning in the brain. Nat. Neurosci. 14, 973-983.

Puram, S. V., Riccio, A., Koirala, S., Ikeuchi, Y., Kim, A. H., Corfas, G. and Bonni,A. (2011b). A TRPC5-regulated calcium signaling pathway controls dendritepatterning in the mammalian brain. Genes Dev. 25, 2659-2673.

Puram, S. V., Kim, A. H., Park, H. Y., Anckar, J. and Bonni, A. (2013). The ubiquitinreceptor S5a/Rpn10 links centrosomal proteasomes with dendrite development inthe mammalian brain. Cell Rep. 4, 19-30.

Quitsch, A., Berhörster, K., Liew, C. W., Richter, D. and Kreienkamp, H. J. (2005).Postsynaptic shank antagonizes dendrite branching induced by the leucine-richrepeat protein Densin-180. J. Neurosci. 25, 479-487.

Ramón y Cajal, S. (1995). Histology of the Nervous System of Man and Vertebrates.New York, NY: Oxford University Press.

Ramos, B., Gaudillière, B., Bonni, A. and Gill, G. (2007). Transcription factor Sp4regulates dendritic patterning during cerebellar maturation. Proc. Natl. Acad. Sci.USA 104, 9882-9887.

Ramos, B., Valín, A., Sun, X. and Gill, G. (2009). Sp4-dependent repression ofneurotrophin-3 limits dendritic branching. Mol. Cell. Neurosci. 42, 152-159.

Redmond, L., Kashani, A. H. and Ghosh, A. (2002). Calcium regulation of dendriticgrowth via CaM kinase IV and CREB-mediated transcription. Neuron 34, 999-1010.

Rosário, M., Schuster, S., Jüttner, R., Parthasarathy, S., Tarabykin, V. andBirchmeier, W. (2012). Neocortical dendritic complexity is controlled duringdevelopment by NOMA-GAP-dependent inhibition of Cdc42 and activation of cofilin.Genes Dev. 26, 1743-1757.

Rosso, S. B., Sussman, D., Wynshaw-Boris, A. and Salinas, P. C. (2005). Wntsignaling through Dishevelled, Rac and JNK regulates dendritic development. Nat.Neurosci. 8, 34-42.

Ruchhoeft, M. L., Ohnuma, S., McNeill, L., Holt, C. E. and Harris, W. A. (1999). Theneuronal architecture of Xenopus retinal ganglion cells is sculpted by rho-familyGTPases in vivo. J. Neurosci. 19, 8454-8463.

Sagasti, A., Guido, M. R., Raible, D. W. and Schier, A. F. (2005). Repulsiveinteractions shape the morphologies and functional arrangement of zebrafishperipheral sensory arbors. Curr. Biol. 15, 804-814.

Sahin, M., Greer, P. L., Lin, M. Z., Poucher, H., Eberhart, J., Schmidt, S., Wright, T.M., Shamah, S. M., O’connell, S., Cowan, C. W. et al. (2005). Eph-dependenttyrosine phosphorylation of ephexin1 modulates growth cone collapse. Neuron 46,191-204.

Saksena, S., Wahlman, J., Teis, D., Johnson, A. E. and Emr, S. D. (2009).Functional reconstitution of ESCRT-III assembly and disassembly. Cell 136, 97-109.

Sasaki, S., Shionoya, A., Ishida, M., Gambello, M. J., Yingling, J., Wynshaw-Boris,A. and Hirotsune, S. (2000). A LIS1/NUDEL/cytoplasmic dynein heavy chaincomplex in the developing and adult nervous system. Neuron 28, 681-696.

Satoh, D., Sato, D., Tsuyama, T., Saito, M., Ohkura, H., Rolls, M. M., Ishikawa, F.and Uemura, T. (2008). Spatial control of branching within dendritic arbors bydynein-dependent transport of Rab5-endosomes. Nat. Cell Biol. 10, 1164-1171.

Schwartz, P. M., Borghesani, P. R., Levy, R. L., Pomeroy, S. L. and Segal, R. A.(1997). Abnormal cerebellar development and foliation in BDNF-/- mice reveals arole for neurotrophins in CNS patterning. Neuron 19, 269-281.

Scott, E. K. and Luo, L. (2001). How do dendrites take their shape? Nat. Neurosci. 4,359-365.

Scott, E. K., Reuter, J. E. and Luo, L. (2003). Small GTPase Cdc42 is required formultiple aspects of dendritic morphogenesis. J. Neurosci. 23, 3118-3123.

Selkoe, D. J., Bell, D. S., Podlisny, M. B., Price, D. L. and Cork, L. C. (1987).Conservation of brain amyloid proteins in aged mammals and humans withAlzheimer’s disease. Science 235, 873-877.

Shalizi, A., Gaudillière, B., Yuan, Z., Stegmüller, J., Shirogane, T., Ge, Q., Tan, Y.,Schulman, B., Harper, J. W. and Bonni, A. (2006). A calcium-regulated MEF2sumoylation switch controls postsynaptic differentiation. Science 311, 1012-1017.

Shalizi, A., Bilimoria, P. M., Stegmüller, J., Gaudillière, B., Yang, Y., Shuai, K. andBonni, A. (2007). PIASx is a MEF2 SUMO E3 ligase that promotes postsynapticdendritic morphogenesis. J. Neurosci. 27, 10037-10046.

Shamah, S. M., Lin, M. Z., Goldberg, J. L., Estrach, S., Sahin, M., Hu, L.,Bazalakova, M., Neve, R. L., Corfas, G., Debant, A. et al. (2001). EphA receptorsregulate growth cone dynamics through the novel guanine nucleotide exchangefactor ephexin. Cell 105, 233-244.

Sharp, D. J., Yu, W., Ferhat, L., Kuriyama, R., Rueger, D. C. and Baas, P. W. (1997).Identification of a microtubule-associated motor protein essential for dendriticdifferentiation. J. Cell Biol. 138, 833-843.

Smith, D. S., Niethammer, M., Ayala, R., Zhou, Y., Gambello, M. J., Wynshaw-Boris, A. and Tsai, L. H. (2000). Regulation of cytoplasmic dynein behaviour andmicrotubule organization by mammalian Lis1. Nat. Cell Biol. 2, 767-775.

Song, Y., Ori-McKenney, K. M., Zheng, Y., Han, C., Jan, L. Y. and Jan, Y. N. (2012).Regeneration of Drosophila sensory neuron axons and dendrites is regulated by theAkt pathway involving Pten and microRNA bantam. Genes Dev. 26, 1612-1625.

Spletter, M. L., Liu, J., Liu, J., Su, H., Giniger, E., Komiyama, T., Quake, S. andLuo, L. (2007). Lola regulates Drosophila olfactory projection neuron identity andtargeting specificity. Neural Dev. 2, 14.

Stegmüller, J. and Bonni, A. (2010). Destroy to create: E3 ubiquitin ligases inneurogenesis. F1000 Biol. Rep. 2, 38.

Stegmüller, J., Konishi, Y., Huynh, M. A., Yuan, Z., Dibacco, S. and Bonni, A.(2006). Cell-intrinsic regulation of axonal morphogenesis by the Cdh1-APC targetSnoN. Neuron 50, 389-400.

Strumpf, D. and Volk, T. (1998). Kakapo, a novel cytoskeletal-associated protein isessential for the restricted localization of the neuregulin-like factor, vein, at themuscle-tendon junction site. J. Cell Biol. 143, 1259-1270.

Sugimura, K., Satoh, D., Estes, P., Crews, S. and Uemura, T. (2004). Developmentof morphological diversity of dendrites in Drosophila by the BTB-zinc finger proteinabrupt. Neuron 43, 809-822.

Sweeney, N. T., Brenman, J. E., Jan, Y. N. and Gao, F. B. (2006). The coiled-coil proteinshrub controls neuronal morphogenesis in Drosophila. Curr. Biol. 16, 1006-1011.

Tahirovic, S. and Bradke, F. (2009). Neuronal polarity. Cold Spring Harb. Perspect.Biol. 1, a001644.

Takashima, S., Becker, L. E., Armstrong, D. L. and Chan, F. (1981). Abnormalneuronal development in the visual cortex of the human fetus and infant with down’ssyndrome. A quantitative and qualitative Golgi study. Brain Res. 225, 1-21.

Tea, J. S. and Luo, L. (2011). The chromatin remodeling factor Bap55 functionsthrough the TIP60 complex to regulate olfactory projection neuron dendrite targeting.Neural Dev. 6, 5.

Tea, J. S., Chihara, T. and Luo, L. (2010). Histone deacetylase Rpd3 regulatesolfactory projection neuron dendrite targeting via the transcription factor Prospero. J.Neurosci. 30, 9939-9946.

Teis, D., Saksena, S. and Emr, S. D. (2008). Ordered assembly of the ESCRT-IIIcomplex on endosomes is required to sequester cargo during MVB formation. Dev.Cell 15, 578-589.

Tolias, K. F., Bikoff, J. B., Burette, A., Paradis, S., Harrar, D., Tavazoie, S.,Weinberg, R. J. and Greenberg, M. E. (2005). The Rac1-GEF Tiam1 couples theNMDA receptor to the activity-dependent development of dendritic arbors andspines. Neuron 45, 525-538.

Ultanir, S. K., Hertz, N. T., Li, G., Ge, W. P., Burlingame, A. L., Pleasure, S. J.,Shokat, K. M., Jan, L. Y. and Jan, Y. N. (2012). Chemical genetic identification ofNDR1/2 kinase substrates AAK1 and Rabin8 uncovers their roles in dendritearborization and spine development. Neuron 73, 1127-1142.

Vessey, J. P., Macchi, P., Stein, J. M., Mikl, M., Hawker, K. N., Vogelsang, P.,Wieczorek, K., Vendra, G., Riefler, J., Tübing, F. et al. (2008). A loss of functionallele for murine Staufen1 leads to impairment of dendritic Staufen1-RNP deliveryand dendritic spine morphogenesis. Proc. Natl. Acad. Sci. USA 105, 16374-16379.

Wässle, H., Peichl, L. and Boycott, B. B. (1981). Dendritic territories of cat retinalganglion cells. Nature 292, 344-345.

Whitford, K. L., Dijkhuizen, P., Polleux, F. and Ghosh, A. (2002). Molecular controlof cortical dendrite development. Annu. Rev. Neurosci. 25, 127-149.

Williams, D. W. and Truman, J. W. (2005). Cellular mechanisms of dendrite pruning inDrosophila: insights from in vivo time-lapse of remodeling dendritic arborizingsensory neurons. Development 132, 3631-3642.

Wills, Z., Bateman, J., Korey, C. A., Comer, A. and Van Vactor, D. (1999). Thetyrosine kinase Abl and its substrate enabled collaborate with the receptorphosphatase Dlar to control motor axon guidance. Neuron 22, 301-312.

Wingate, R. J. and Thompson, I. D. (1994). Targeting and activity-related dendriticmodification in mammalian retinal ganglion cells. J. Neurosci. 14, 6621-6637.

Winter, C. G., Wang, B., Ballew, A., Royou, A., Karess, R., Axelrod, J. D. and Luo,L. (2001). Drosophila Rho-associated kinase (Drok) links Frizzled-mediated planarcell polarity signaling to the actin cytoskeleton. Cell 105, 81-91.

Wong, W. T., Faulkner-Jones, B. E., Sanes, J. R. and Wong, R. O. (2000). Rapiddendritic remodeling in the developing retina: dependence on neurotransmission andreciprocal regulation by Rac and Rho. J. Neurosci. 20, 5024-5036.

Wu, J. I., Lessard, J., Olave, I. A., Qiu, Z., Ghosh, A., Graef, I. A. and Crabtree, G.R. (2007). Regulation of dendritic development by neuron-specific chromatinremodeling complexes. Neuron 56, 94-108.


DEVELO

PMENT

Yamada, T., Yang, Y. and Bonni, A. (2013). Spatial organization of ubiquitin ligasepathways orchestrates neuronal connectivity. Trends Neurosci. 36, 218-226.

Yang, Y., Kim, A. H. and Bonni, A. (2010). The dynamic ubiquitin ligase duo: Cdh1-APC and Cdc20-APC regulate neuronal morphogenesis and connectivity. Curr.Opin. Neurobiol. 20, 92-99.

Yang, W. K., Peng, Y. H., Li, H., Lin, H. C., Lin, Y. C., Lai, T. T., Suo, H., Wang, C. H.,Lin, W. H., Ou, C. Y. et al. (2011). Nak regulates localization of clathrin sites inhigher-order dendrites to promote local dendrite growth. Neuron 72, 285-299.

Ye, B., Petritsch, C., Clark, I. E., Gavis, E. R., Jan, L. Y. and Jan, Y. N. (2004).Nanos and Pumilio are essential for dendrite morphogenesis in Drosophilaperipheral neurons. Curr. Biol. 14, 314-321.

Ye, B., Zhang, Y., Song, W., Younger, S. H., Jan, L. Y. and Jan, Y. N. (2007).Growing dendrites and axons differ in their reliance on the secretory pathway. Cell130, 717-729.

Yu, X. and Malenka, R. C. (2003). Beta-catenin is critical for dendritic morphogenesis.Nat. Neurosci. 6, 1169-1177.

Yu, W., Cook, C., Sauter, C., Kuriyama, R., Kaplan, P. L. and Baas, P. W. (2000).Depletion of a microtubule-associated motor protein induces the loss of dendriticidentity. J. Neurosci. 20, 5782-5791.

Zheng, Y., Wildonger, J., Ye, B., Zhang, Y., Kita, A., Younger, S. H., Zimmerman,S., Jan, L. Y. and Jan, Y. N. (2008). Dynein is required for polarized dendritictransport and uniform microtubule orientation in axons. Nat. Cell Biol. 10, 1172-1180.

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