Developmental neurobiology: A destructive switch for neurons
Transcript of Developmental neurobiology: A destructive switch for neurons
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cosmos are in their infancy4,5. The detection oftransient emission is important because it provides a window on diverse astrophysicalobjects, from variable stars and stellar explo-sions to the mergers of compact stellar rem-nants. Even more exciting is the potential fordiscovering new, unanticipated phenomena.The intriguing initial data hint at much moreto come: imagine what we might find if wecould monitor the sky for optical bursts justminutes long, and a million times fainter thanthose currently spotted.
By using larger, 4-metre-aperture telescopesto peer deeper into the distant Universe whilestill surveying a large volume, a few short-lived,faint optical bursts without apparent precursorobjects have already been spotted. The DeepLens Survey, for example, which searched anarea of sky of 20 square degrees using theNational Science Foundation’s sister Blancoand Mayall telescopes in Chile and Arizona,found three blue flares with lifetimes shorterthan 1,000 seconds. Follow-up spectroscopy,however, revealed one of these to be a flaringfaint red dwarf star in our Galaxy6.
Using the twin 10-metre-aperture Keck telescopes on the summit of Mauna Kea, on Hawaii, Kulkarni and Rau1 have obtainedspectra of the remaining two mysterious flar-ing objects. Their conclusion is that they tooare blue flares of red dwarf stars (Fig. 1).Extrapolating to the next generation of wide-field surveys, which will probe deeper into the distant Universe for transient events, theimplication is that we will be peering througha foreground confusion of perhaps 7,000
flaring dwarf stars in our Galaxy each year.Help might be at hand. Taking advantage of
advances in scientific computing that allow thefast processing of vastly increased quantities of data, as well as breakthroughs in large-scale optics and microelectronics, the LargeSynoptic Survey Telescope (LSST)7 has beendesigned to overcome many of these difficul-ties. It will open up the time domain in astron-omy by going wide, fast and deep, observingthe entire visible sky 2,000 times in six colours,and producing up to 30,000 gigabytes of dataevery night. Cosmic cartography will becomecosmic cinematography.
The LSST will be capable of separating dis-tant high-energy events from blue flares onnearby stars by identifying the host star, which
would emit light at a near-infrared wavelength.More generally, the thousandfold increase inbreadth and depth of view that can be surveyedduring any one period will virtually guaranteethe discovery of new transient phenomena. Anew view of our Universe is in sight. ■
J. Anthony Tyson is in the Department of Physics,University of California, Davis, California 95616,USA.e-mail: [email protected]
1. Kulkarni, S. R. & Rau, A. Astrophys. J. 644, L63–L66 (2006).2. Akerlof, C. et al. Nature 398, 400–402 (1999).3. Wozniak, P. R. et al. Astrophys. J. 642, L99–L102 (2006).4. Paczynski, B. Publ. Astron. Soc. Pacif. 112, 1281–1283 (2000).5. Colgate, S. A., Moore, E. P. & Carlson, R. A. Publ. Astron. Soc.
Pacif. 87, 565–575 (1975).6. Becker, A. C. et al. Astrophys. J. 611, 418–433 (2004).7. www.lsst.org
the developing brain seem to provide the spatial cues that position the birth of themature neuron. There also seem to be intrin-sic timing mechanisms within neuroblasts that stop the cell-division cycle and trigger the activation of the programme that extendsthe axon.
In this issue, Iavarone and colleagues1
(Lasorella et al., page 471) provide a crucialinsight into this triggering mechanism. Theauthors show that a well-known regulator ofexit from mitosis — the anaphase-promotingcomplex — directly modifies and initiates thedestruction of Id2, a regulator of gene expres-sion. This protein inhibits a protein complexcalled E12–E47 that initiates the expression ofneuron-specific genes2. The authors also show
Figure 1 | Optical flash: cosmic or local? A short-lived optical flare is caught on camera in this sequenceof Deep Lens Survey image mosaics taken with the Blanco telescope at the Cerro Tololo InteramericanObservatory in Chile. a, b, Images taken before and during the flare. c, Difference between images in aand b; the flaring object alone is seen. Kulkarni and Rau’s spectroscopic results1 reveal a faint red dwarfstar in our Galaxy at that position. Such flaring foreground stars could confound searches for faintbursts of light from the distant Universe, unless images at wavelengths in the near infrared are alsoobtained as part of future surveys. (Image courtesy of A. Becker et al.5.)
a b c
DEVELOPMENTAL NEUROBIOLOGY
A destructive switch for neuronsPeter K. Jackson
In the developing nervous system, tremendous multiplication and diversification of cells elaborate the exquisite pattern of the brain. But how do cells shift from early proliferation to assume their mature states?
Control of cell division in the developing ner-vous system is a highly orchestrated processthat sets up the patterns for the extendedstructure of the brain. In the embryonic brain,the division of neuroblasts — the precursors of neurons — occurs in specific proliferativezones. From these zones, neuroblasts undergomultiple rounds of cell division (mitosis) whilemigrating considerable distances, producingclusters of neuronal precursor cells. At specifictimes and sites in the developing brain, neuroblasts stop dividing and mature intoneurons. The post-mitotic cells extend axonalprocesses, the elongated nerve fibres that formsynapse junctions to communicate with otherneurons. Although the details are not wellunderstood, specific extracellular signals in
that the activation of E47, following thedestruction of Id2, may turn on genes that prepare the axon for later stages of neuronalmaturation. Together, these findings open anew link between the mechanism that causescells to cease division and the activation of thegene-expression programme that directs neu-ronal function (Fig. 1, overleaf).
The implications of this work extend wellbeyond the development of the nervous system,as the E12 and E47 proteins are members of thebasic helix-loop-helix (bHLH) DNA-bindingproteins that drive cellular differentiation inmany cell lineages2. These proteins function asheterodimers, where a tissue-specific bHLH,such as the E47 protein, pairs with the ubiqui-tous bHLH subunit E12 to activate a cell-type-specific gene-expression programme.
A family of inhibitors called ‘inhibitor of differentiation’ (Id) proteins also contain thebHLH domain, but lack the domain requiredfor DNA binding. So the Id proteins bind tobHLH factors and quench their ability to acti-vate transcription (gene expression). In severalcell lineages, inhibition of the bHLH-drivendifferentiation programme by Id proteinsmaintains cells in the unspecialized, dividingstate. Thus, a change in the balance between
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Id proteins and bHLH transcriptional activitymay be at the heart of the transition from celldivision to differentiation in many tissues. Butwhat triggers that transition has not been clear.The work by Iavarone and colleagues1 suggeststhat destruction (proteolysis) of the Id2 pro-tein may be the key. So, what’s the destroyer,and how is it tied to the cell-division cycle?
In cell division, the periodic accumulationand destruction of proteins called mitoticcyclins forms the central clock directing cell division. When cyclin accumulates to sufficient levels, it triggers the activation of the central events in mitosis, including the segregation of chromosomes into daughtercells and the exit from the cell cycle. At theheart of the mechanism for mitotic exit is the anaphase-promoting complex/cyclosome(APC/C)3. This complex belongs to a largeclass of enzymes that tag specific proteins witha label that targets them for degradation4. TheAPC/C complex directs the destruction ofcyclin and other important mitotic regulators,thereby initiating the mitotic exit. For APC/Cto cause exit from the division cycle, it requiresa specific activator called Cdh1. What was lessclear was whether APC/CCdh1 mostly elimi-nates general cell-division regulators, such ascyclins, or whether it has more specific targetsthat inhibit cell differentiation after mitosis,such as Id2.
Id2 is expressed in neuroblasts of severalneural lineages, suggesting that it has a centralrole in neural development2. To examine whatthis might be, Iavarone and colleagues purifiedproteins that associate with Id2 in embryonicmouse brains. Surprisingly, they found com-ponents of APC/C. Previous studies had iden-tified substantial amounts of APC/CCdh1 inpost-mitotic neurons in the adult brain5, butthis is the first demonstration that it binds afunctionally pivotal target in these cells.
A look at the sequence of Id2 turned up aregion known as the destruction box that isrequired for APC/C to bind to its substrates6
and to mark that protein for destruction3. Theauthors show that Id2 is indeed degraded inmouse embryonic neuroblasts after the cellsexited mitosis, and that this degradationrequires APC/CCdh1 and an intact destructionbox. It will be of interest to see whether APC/Cand Id2 destruction have a role in adult, dam-aged or regenerating neural tissues.
Inhibition of Cdh1 causes overly elongatedaxons7, suggesting that Cdh1 triggers destruc-tion of a regulator of axon growth. This regu-lator was unknown, but Id2 was a strongcandidate. Iavarone and colleagues1 now showthat inactivation of Cdh1 in post-mitotic neurons stops the destruction of Id2. Also,expression of an Id2 mutant with a defectivedestruction box (which is therefore not brokendown) stimulated a prolonged axon out-growth in cerebellar granule neurons, corticalneurons and neuroblast cell lines. So, Id2 isclearly a central factor that is destroyed inpost-mitotic neurons to restrain axon growth
— the next step in neuronal maturation.Another possible APC/C substrate, the tran-scriptional regulator SnoN, is also a target ofCdh1 in neurons8, but the relative importanceof SnoN and Id2 destruction will require fur-ther study.
If blocking Id2 destruction causes pro-
longed axon outgrowth, what of the E47 tran-scription factor that Id2 inhibits? Does E47reverse axon growth? Iavarone and colleaguesconfirm that overexpressing E47 in neuronsdid indeed reverse the ability of Cdh1 inacti-vation to prolong axon outgrowth. So the E47transcriptional response seems to be a majordeterminant of the programme limiting axonoutgrowth (Fig. 2). The authors identify a listof candidate genes that might link E47 to axongrowth control, including — provocatively —several genes that are implicated in theinhibitory and repellent signalling for axongrowth. These include a secreted molecule(Sema3F), a cell surface receptor ligand(Jagged-2), and some neuronal receptors(Nogo, Unc5A and Notch1).
These results suggest a scenario of neuronaldifferentiation such that, as Id2 is beingdestroyed and the axon is extending, the cellsprepare for axon growth inhibition by thetranscriptional activation of an inhibitory pro-gramme (Fig. 2). One of the candidates for thatinhibitory programme would be the myelin-inhibitory signals, which block axon out-growth. Indeed, Iavarone et al. show that theId2–E47 balance modulates this inhibitoryprogramme.
This study1 has strong implications for bothneural biology and differentiation controlmore generally. In neurons, the targets of E47may shed considerable light on the regulationof axon outgrowth. Other bHLH factors,including the NeuroD regulator, may be regu-lated by Id2. Whether there are other tran-scriptional regulatory programmes under Id2and/or APC/C control is also still unclear,although APC/C has been linked to axon target finding and synapse maturation9,10.
Although APC/C-dependent destruction ofId2 is crucial in the transition to the post-mitotic programme, the specific timing andspatial signals that may trigger that decisionare not well understood. There is considerablereason to suspect that polarity signals receivedby the mitotic cell might determine where andwhen the axon extends, possibly through reg-ulating the activation of the APC/C towardssubstrates such as Id2. These studies linkingcell-cycle exit, polarity and the differentiationof neurons may indeed have considerableextensions. ■
Peter K. Jackson is in the Department ofPathology, Stanford University School ofMedicine, 300 Pasteur Drive, Stanford, California94305, and at Genentech Inc., 1 DNA Way, San Francisco, California 94080, USA.e-mail: [email protected]
1. Lasorella, A. et al. Nature 442, 471–474 (2006).2. Yokota, Y. Oncogene 20, 8290–8298 (2001).3. Peters, J. M. Mol. Cell 9, 931–943 (2002).4. Jackson, P. K. et al. Trends Cell Biol. 10, 429–439 (2000).5. Gieffers, C. et al. Proc. Natl Acad. Sci. USA 96, 11317–11322
(1999).6. Yamano, H. et al. Mol. Cell 16, 137–147 (2004).7. Konishi, Y. et al. Science 303, 1026–1030 (2004).8. Stegmuller, J. et al. Neuron 50, 389–400 (2006). 9. Juo, P. & Kaplan, J. M. Curr. Biol. 14, 2057–2062 (2004). 10. van Roessel, P. et al. Cell 119, 707–718 (2004).
Figure 1 | Protein destruction in post-mitoticneurons. The work by Iavarone and colleagues1
suggests that following the final neuroblast celldivision (mitosis), cyclins and other mitoticregulators are marked for destruction by theCdh1 form of the anaphase-promotingcomplex/cyclosome (APC/CCdh1). In the ensuingpost-mitotic period, destruction of the Id2transcriptional regulator allows activation of itstarget, the E47–E12 transcriptional regulator.Transcription of crucial neuronal genes followsand the gene products may both promote andeventually limit axon growth, but also promotelater events in neuronal maturation.
Figure 2 | A model for destruction of inhibitors ofneuronal differentiation. Spatial and temporalcues may initiate mitosis in neuroblasts.Activation of the APC/C in mitosis triggersdestruction of cyclin, to allow mitotic exit, and ofId2, to allow activation of the neuron-specific E47transcription factor. Activation of E47 promotesthe transcriptional activation of several factorsthat limit axon growth (Nogo receptor, Sema3F,Unc5A, Notch1, Jagged-2), but possibly otherfactors that regulate axon growth anddifferentiation.
Mitoticexit
Cyclindestruction
APC/CCdh1 activity
Id2 destruction
Axonal growth
Activation of bHLHand neuronal genes
Neu
robl
ast d
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ions
Axonoutgrowth
Neuronalmaturation
APC/C
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?Other neuronal functions(SnoN, pathfinding,synaptic maturation)
Factors regulating axongrowth/differentiation
Signals limitingaxon growth
Id2 destruction
E47 transcription
Nogo receptorSema3FUnc5ANotch1Jagged-2
Mitosis
Spatial and temporal cues for neuronal differentiation
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