The Yin and Yang of Sox Proteins- Activation and Repression in Development and Disease

8/14/2019 The Yin and Yang of Sox Proteins- Activation and Repression in Development and Disease

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Review

The Yin and Yang of Sox Proteins:Activation and Repression in Developmentand Disease

Li-Jin Chew and Vittorio Gallo*

Center for Neuroscience Research, Childrens National Medical Center, Washington, DC

The general view of development consists of the acqui-sition of committed/differentiated phenotypes followinga period of self-renewal and progenitor expansion. Lin-eage specification and progression are phenomena ofantagonistic events, silencing tissue-specific geneexpression in precursors to allow self-renewal and mul-tipotentiality, and subsequently suppressing prolifera-tion and embryonic gene expression to promote therestricted expression of tissue-specific genes duringmaturation. The high mobility group-containing Soxfamily of transcription factors constitutes one of theearliest classes of genes to be expressed during em-bryonic development. These proteins not only are indis-pensable for progenitor cell specification but also arecritical for terminal differentiation of multiple cell typesin a wide variety of lineages. Sox transcription factorsare now known to induce or repress progenitor cellcharacteristics and cell proliferation or to activate theexpression of tissue-specific genes. Sox proteins fulfilltheir diverse functions in developmental regulation bydistinct molecular mechanisms. Not surprisingly, inaddition to DNA binding and bending, Soxtranscriptionfactors also interact with different protein partners tofunction as coactivators or corepressors of downstreamtarget genes. Here we seek to provide an overview ofthe current knowledge of Sox gene functional mecha-nisms, in an effort to understand their roles in bothdevelopment and pathology. VVC 2009 Wiley-Liss, Inc.

Key words: HMG; SOX; development; transcription;Wnt; interactions

The Sox protein family of transcription factors hasbeen identified as one of the most important groups ofdevelopmental regulators both in vertebrates and ininvertebrates (Bowles et al., 2000; Wegner, 1999). Thebiological functions of these proteins during embryonicand postnatal development have been defined in a varietyof tissues and cell types. Furthermore, the roles of Soxtranscription factors are also being investigated in diseaseand in cell repair. The Sox family has no single biological

function, and, among their multiple roles, Sox transcrip-tion factors induce or suppress progenitor cell properties,such as proliferation and multipotentiality, or initiate dif-ferentiation programs by activating the expression of tis-sue-specific genes. Despite overlapping functions withinfamilies, each Sox protein modulates a unique set of tar-get genes in a specific cell type. There is already a largebody of evidence supporting the generation of specificSox-mediated cellular responses through mechanisms ofDNA bending and binding and recruitment of differentinteracting protein partners to function as coactivators orcorepressors of downstream target genes.

As is expected of developmental regulators withmultiple functions, Sox transcription factors display verydiverse tissue-specific expression patterns during embry-onic and postnatal development. These expression pat-

terns are modified not only during normal developmentbut also in a variety of pathological states, to the extentthat some members of the Sox family are consideredimportant diagnostic markers of childhood brain tumors(de Bont et al., 2008).

All these findings continue to raise a number ofimportant issues that are crucial to understanding therelationship between the molecular properties of Soxproteins and the extreme diversity of their functionalroles. The molecular mechanisms of gene activation orgene repression mediated by Sox proteins and the func-

Contract grant sponsor: National Institutes of Health; Contract grant

number: R01NS045702; Contract grant number: R01NS1056427; Con-

tract grant number: IDDRC P30HD40677; Contract grant sponsor:

National Multiple Sclerosis Society; Contract grant number: RG4019;

Contract grant sponsor: European Leukodystrophy Association.

*Correspondence to: Vittorio Gallo, PhD, Center for Neuroscience

Research, Childrens Research Institute, Room 7643, Childrens

National Medical Center, 111 Michigan Avenue, Washington, DC

20010. E-mail: [email protected]

Received 20 October 2008; Revised 1 April 2009; Accepted 8 April

2009

Published online 12 May 2009 in Wiley InterScience (www.

interscience.wiley.com). DOI: 10.1002/jnr.22128

Journal of Neuroscience Research 87:32773287 (2009)

' 2009 Wiley-Liss, Inc.


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tional redundancy of these transcription factors representimportant areas for current and future research. In thisMini-Review, we highlight functional aspects of Soxproteins in the context of developmental events, with aparticular focus on Sox proteins as transcriptional activa-tors and repressors, in an effort to understand their rolesin both development and disease.

THE Sox SUBFAMILY WITHIN THE HMGSUPERFAMILY: CLASSIFICATION INTO

Sox SUBGROUPS AND SOMEMOLECULAR PROPERTIES

The Sox transcription factors bind to the minorgroove in DNA and were first identified based on molec-ular conservation of the 79-amino-acid HMG (high mo-bility group) DNA binding domain found in the gene forthe mammalian testis-determining factor SRY (Gubbayet al., 1990). Almost all Sox (SRY-BOX) genes display atleast 50% amino acid similarity with the Sry HMG box.To date, the total number of Sox transcription factorsidentified is approximately 30 (20 in humans and mice,and eight in Drosophila), subgrouped into 10 distinct fami-lies (AJ), based not only on homology within the HMGdomain and other structural motifs but also on functionalproperties (Schepers et al., 2002). These groups include:A, Sry; B, Sox1, -2, -3, -14, and -21; C, Sox4, -11, and-12; D, Sox5, -6, and -13; E, Sox8, -9, and -10; F, Sox7,-17, and -18; G,Sox15and -20; and H,Sox30. The exis-tence of two new subgroups (I and J) has been postulated,including Xenopus Sox31 and C. elegans SoxJ, respectively(Bowles et al., 2000). A thorough molecular analysis ofthe evolutionary history of the SOX family was based onthe entire number of available HMG domain sequencesand full-length protein sequences (Wegner, 1999; Bowleset al., 2000). This study demonstrated that the majority ofthe SOX subfamilies defined in vertebrates were alsorepresented in invertebrates by a single Sox gene.

All Sox factors recognize a similar DNA bindingmotif A/T

A/TCAAA/TG, but their amino acid sequences

outside the HMG domain are highly variable and displaydomains that favor binding with other regulatory proteinpartners. Molecular interactions with other transcriptionalregulators are crucial for eachSOX factor to recognize aspecific target gene, because each protein of this family isexpressed in many different cellular contexts, and a spe-cific cell type can coexpress manySOX factors (Wegner,

1999). SOX proteins can form stable transcription factorcomplexes with a variety of coregulators to activate orrepress gene transcription by modulating promoter activ-ity. A typical example of this cooperative interaction isthe demonstration that SOX2 and PAX6 activate tran-scription of the lens-specificd-crystallingene by acting onits DC5 enhancer (Kamachi et al., 2001). There are alsoseveral examples ofSOX/OCT complexes that regulateexpression of different genes. SOX2 and SOX3 interactwith Oct3/4 to regulate Fgf4, UTF1, and osteopontin geneexpression in the embryo (Yuan et al., 1995; Botquinet al., 1998; Nishimoto et al., 1999; Kamachi et al.,

2000). SOX and Oct binding sites are necessary forenhancer activity and cell specificity of the Hoxb1 gene,which encodes a protein involved in hindbrain pattern-ing. A single SOXprotein can also simultaneously recruitmore than one transcription factor to regulate geneexpression from a single promoter or enhancer (Ma et al.,2000) or can promote binding with transcriptionalrepressors to promoters, as demonstrated by the SOX6/CtBP2interaction (Murakami et al., 2001).

It is currently thought that the HMG domain itselfplays a crucial role not only in the DNA-binding ofSOXfactors but also in their interaction with other tran-scriptional coregulators and in nuclear import (Wilsonand Koopman, 2002). However, because HMG domainsare interchangeable between SOX factors (Bergstromet al., 2000), other parts of the protein outside the HMGdomain are likely to play a major role in selecting specificprotein partners and generate cell- and developmentalstage-specific functions for SOX transcription factors(Wilson and Koopman, 2002). A recent study of SoxEbinding partners revealed specific interactions withOct3/4, C/EBP, Olig2, Pax3, and SP1 but not the receptorsfor estrogen or thyroid hormone (Wibmuller et al.,2006), which supports the pleiotropic nature of SOXprotein activity, although the manner in which cell typeor temporal specificity is determined is not understood.

Sox PROTEINS IN MECHANISMSINVOLVING FUNCTIONAL ANTAGONISM

DURING DIFFERENTIATION

SoxB1(Sox13)

Although it is well established that neural progeni-tors in the CNS are prevented from premature differen-tiation, the mechanism by which this occurs is poorlyunderstood. The expression ofSoxB1 members in divid-ing CNS progenitor cells, and not in those expressingdefinitive neuronal markers such as NeuN, Tuj1, andLim2 (Bylund et al., 2003), strongly suggests a role forthese SoxB1 transcription factors in the maintenance ofthe progenitor state. Indeed, inhibition ofSox2 signalingresulted in enhanced neuronal differentiation (Grahamet al., 2003). Consistently with this hypothesis, it wasdemonstrated that these Sox genes 13, with some mea-sure of redundancy (Graham et al., 2003), preventedneurogenesis by antagonizing the function of proneuralbHLH proteins, namely, neurogenin (Ngn), and were

down-regulated once progenitor cells left the cell cycle(Bylund et al., 2003). SoxB1 members bear transactiva-tion domains, and the conclusion that they function astranscriptional activators was revealed by a hybrid HMGdomain containing the Engrailed protein repressor mod-ule. HMG-VP16 activator suppressed neuronal differen-tiation similarly to intact Sox13, whereas HMG-EnRgenerated postmitotic neurons (Bylund et al., 2003).These Sox genes collectively specify and maintain stemcells and progenitors, but differential functions for themare being discovered in more recent studies. AlthoughSox13 are down-regulated in mature neurons, the

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expression ofSox1, though not required for neurospheregeneration, was shown to be necessary for the differentia-tion of neural progenitors from the ganglionic eminenceand dorsal telencephalic wall into GAD651 neuronalprogenitors (Kan et al., 2007). Sox1-null mutant micealso lack telencephalic neurons that constitute the ventralstriatum (Ekonomou et al., 2005). Indeed, only Sox1,not Sox2or -3, was shown to be able to induce neuronallineage commitment by repressing Hes1 gene expression(Kan et al., 2004). In addition to up-regulating the tran-scription of Ngn1, Sox1 suppresses beta-catenin-mediatedTCF/LEF signaling to attenuate the Wnt pathway andpromotes cell cycle exit, leading to neuronal cell differen-tiation (Kan et al., 2004). Like Sox1, Sox3 is transientlyexpressed by proliferating and differentiating neural pro-genitors in the olfactory bulb and dentate gyrus, whilepersisting in specific postmitotic neuronal populations(Wang et al., 2006), although the mechanism by whichSox3 induces neurogenesis is unclear.

In contrast to Sox1 or Sox3, Sox2 has been moreconsistently associated with multipotentiality and progen-itor cell proliferation (Rex et al., 1997). Sox2 expressionis itself subject to repression by histone deacetylase activ-ity (Lyssiotis et al., 2007), which is important for oligo-dendrocyte maturation (Shen et al., 2005, 2008). Sox2expression was restricted to proliferating progenitor cells,and its overexpression was observed to inhibit neurogen-esis (Bani-Yaghoub et al., 2006). Sox2 is thought tomaintain cellular proliferative potential through the up-regulation of Notch1 (Bani-Yaghoub et al., 2006) forthe purpose of generating sufficient numbers of progeni-tors (Ellis et al., 2004). Sox2-deficient neural stem cells,however, remain multipotent, likely as a result of com-pensation by Sox3, but the capacity for generating suffi-cient neurons is greatly reduced (Miyagi et al., 2008).This notion of progenitor maintenance is in agreementwith the finding of high levels ofSox2 expression in glialtumors of astroglial, oligodendroglial, and ependymal lin-eages (Phi et al., 2008), but not in neuronal tumors.Possible molecular mechanisms have been offered fromstudies in nonneural systems and in embryonic stemcells, implicating the regulation of cyclin D1 expressionas a primary function of Sox2 activity. In breast cancercells, modulation of Sox2 activity by overexpression orknockdown had little effect on other cell cycle-regulatedgenes, including cyclin D3, cyclin E, p21Cip, and p27Kip

(Chen et al., 2008). The authors also demonstrated that

Sox2 and beta-catenin interact directly to activate thecyclin D1 proximal promoter synergistically (Chen et al.,2008). In embryonic stem cells, Sox2 and Oct4 boundto the promoter of miR-302aa cluster of miRNAsspecifically expressed in stem cells and pluripotentcellsto stimulate its expression. miR-302a repressedthe translation of cyclin D1 and promoted a decrease inG1 cells and an increase in S-phase cells (Greer Cardet al., 2008). These observations are consistent with thenotion of Sox2 as a promitotic regulator, and, althoughcell cycle regulation alone is insufficient to alter cell-fatedecisions through the modulation of cyclin D1 expres-

sion (Lobjois et al., 2008), SoxB1 proteins function tomaintain neural precursors by mechanisms that mayinvolve the Notch pathway. Sox2 and Sox1, respectively,activate (Bani-Yaghoub et al., 2006) and inhibit (Kanet al., 2004) Notch signaling, but there is also evidencethat SoxB1 and Notch inhibit neuronal maturation bydistinct mechanisms (Holmberg et al., 2008).

SoxB2(Sox14, Sox21)

The SoxB2 group possesses repression domains,and Sox21 and Sox14 inhibit the activation of the delta-crystallin DC5 enhancer to different extents (Uchikawaet al., 1999). Sox21 promotes neurogenesis by counter-acting the activities of Sox13, and the ability of proneu-ral proteins to promote lineage progression relies ontheir ability to up-regulate Sox21 expression (Sandberget al., 2005). Ngn2 stimulates Sox21 expression, and thelatter in turn is associated with increased cell cycle exit,although the detailed mechanism is presently unknown.

SoxC(Sox4, Sox11, Sox12)

As activators, Sox4 and Sox11 have been shown toinduce a neuronal phenotype in immature neuronal pre-cursors of the early chicken embryo (Bergsland et al.,2006) in a manner that is independent of cell cycle exit. Inthe oligodendrocyte lineage, however, prolonged expres-sion ofSox4 in vivo under the control of the MBPpro-moter results in reduced and delayed myelin gene expres-sion in the spinal cord (Potzner et al., 2007). High levelsofSox11 are also found in human gliomas, in accordancewith the degree of cell dedifferentiation (Weigle et al.,2005). In further support of an inhibitory role ofSoxCinoligodendrocyte development, the ablation ofYY1, which

resulted in hypomyelination, also increased the levels ofoligodendroglial-lineage repressors, including Sox11 (Heet al., 2007). These SoxC proteins thus appear to possessopposing effects on neuronal vs. glial differentiation, pro-moting one and repressing the other. The mechanism ofSoxC protein repression is not understood, but, becauseSoxC proteins, unlike SoxD proteins, do not interferewith Sox10-dependent up-regulation of myelin genes(Potzner et al., 2007), it is believed that the SoxC-inducedhypomyelination is an indirect effect on theMBPgene.

SoxD (Sox5, L-Sox5, Sox6, Sox13)

Members of this group possess an HMG domain but

are missing transactivation domains, suggesting roles instructural organization in gene expression.Sox5and Sox6are essential for neuronal and chondrocyte development,and Sox6 is also an important enhancer of erythropoiesis(Dumitriu et al., 2008). Sox5 was recently found to pre-vent the premature development of later-born neuronsand thus regulates the timing of neocortical neuronal sub-types (Lai et al., 2008). Sox5promotes cell proliferationby repressing the expression of SPARC (Huang et al.,2008), a protein believed to be a tumor suppressor. Inchondroblast differentiation, Sox5 and Sox6promote thedevelopment of a proliferating pool of chondroblasts and

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act by down-regulating Indian hedgehog signaling andthe expression ofFGFR3and Runx2(Smits et al., 2004).

In neural crest development, Sox5 is expressed inearly neural crest cells and continues to be expressed inmelanocytes, but its loss does not affect melanoblast gen-eration. However, the loss of Sox5 rescues melanoblastgeneration in Sox10-reduced mice. Sox5 binds to andrepresses melanocytic target genes ofSox10, such as Mitf and Dct (Stolt et al., 2008). Sox5 alone did not modulatethese genes directly but did so only in the presence ofSox10 (see below underSoxEproteins). Competition forthe same DNA binding site is possible, but it appearsmore likely that, in situations with multiple Sox recogni-tion sites, the recruitment of corepressors, C-terminalbinding protein 2 (CtBP2) and HDAC1 to the pro-moters of Mitf and Dct genes, could be more effective.Sox5 does not function exclusively as a corepressor butalso recruits coactivators to Sox9 target genes in chon-drocytes (Hattori et al., 2008).

Sox6 promotes cardiomyocyte differentiation, anevent associated with the down-regulation of an L-typeCa21 alpha1c gene. There are eight consensus Sox rec-ognition sites in 1.6 kb of the Ca21 alpha1c promoter,and overexpression of Sox6 suppresses reporter expres-sion in constructs bearing this promoter region (Cohen-Barak et al., 2003). Prtb (proline-rich transcript of thebrain), which interacts with Sox6, represses the activityof the alpha1c gene promoter alone, as does Sox6 alone,but, interestingly, repression of reporter expression isabolished by coexpression of Prtb with Sox6 (Cohen-Barak et al., 2003). This suggests that Prtb and Sox6antagonize each other as repressors. Skeletal muscle de-velopment consists of two successive waves of myogene-sis, embryonic and fetal, generating slow and fast fibers,respectively. Sox6 mutant mice show increased slowfiber type-specific gene expression and reduced fast fibergene expression (Hagiwara et al., 2005). Sox6 has beendemonstrated to repress the transcription of slow fibertype-specific genes typified by the myosin heavy chain-beta (MyHCb), slow isoform (Hagiwara et al., 2007).

During erythropoiesis, definite erythroid cells in thefetal liver express adult beta globins, while the epsilongene is silenced. Sox6 represses embryonic epsilon geneexpression by directly binding its promoter (Yi et al.,2006). Sox6 has been shown to silence other targets invarious systems: 1) the Fgf-3 promoter through therecruitment of a corepressor, CtBP2 (Murakami et al.,

2001); 2) the insulin IIgene by serving as an interactingcorepressor of the homeobox factorPDX1 (Iguchi et al.,2005); and 3) the cyclin D1 promoter by interacting withbeta-catenin and histone deacetylase (Iguchi et al., 2007).

Sox13is expressed at high levels in a subset of neuralprogenitor cells as they exit from the cell cycle andmigrate away from the ventricular zone (Wang et al.,2005). In T-lymphocyte differentiation, Sox13 promotesthe development of gammaDelta lineage from progenitorswhile suppressing differentiation to the alphaBeta lineage(Melichar et al., 2007). This fate determination was medi-ated through inhibition ofWntsignaling, not by interact-

ing with beta-catenin per se but instead by antagonizingits coactivator T-cell factor 1 (TCF1). Sox13 also down-regulated a known TCF1 target gene, Ly49a, in EL4 Tcells. Finally, Sox13-null mice showed enhanced rates ofthymocyte proliferation, indicating thatSox13antagonismof Wnt/TCF signaling mediated both lineage commit-ment and proliferative arrest (Melichar et al., 2007).

SoxE(Sox8, Sox9, Sox10)

SoxE proteins promote neural crest progenitor for-mation as well as differentiation of neural crest-derivedmelanoblasts and glia (Bondurand et al., 2000; Britschet al., 2001; Kim et al., 2003; Hong and Saint-Jeannet,2005; Taylor and LaBonne, 2005), oligodendrocyte dif-ferentiation (Stolt et al., 2002, 2003, 2004), and cartilagedevelopment (Lefebvre et al., 1998; Sekiya et al., 2000;Akiyama et al., 2002).

SoxE, in particularSox9, acts in two phases of neu-ral crest development: promotion of neural crest proper-ties and of glial and melanocyte fate, while suppressingneuronal fates (Cheung and Briscoe, 2003; Kim et al.,2003). Sox9 suppresses the expression of neuronalmarkers Pax6, Pax7, Nkx6, and Irx3, and its mode ofaction appears to be independent ofBMPorWnt signal-ing (Cheung and Briscoe, 2003). In the neural crest,Sox10acts to maintain characteristics of multipotentialityin neural crest stem cells (Kim et al., 2003) and modu-lates neural crest progenitor properties by promotingglial development (Britsch et al., 2001) and by overcom-ing the antigliogenic and antineurogenic activities ofBMP2 and TGFbeta, respectively (Kim et al., 2003). Theloss ofSox10from Schwannoma cells promotes differen-tiation into myofibroblasts with carbachol-stimulatedcontraction and calcium transients, indicating the roleand bias of this SoxE protein in repressing myofibro-blast-specific genes in a cell system known to transdiffer-entiate into several derivatives (Roh et al., 2006).

SoxE proteins are responsible for oligodendrocytespecification and maturation, with Sox9 and Sox10play-ing critical roles in determining progenitor fate commit-ment and terminal differentiation. Initially, both proteinsappear to function redundantly in oligodendrocyte pre-cursors, but Sox9, whose expression precedes that ofSox10 and Sox8, has been shown to be essential for theneuron-glia fate switch, suppressing the formation of spi-nal cord motoneurons, V2 interneurons, and gray matter

astrocytes. On the other hand, Sox10, which continuesto be expressed in developing oligodendrocytes andastrocytes, is essential for myelination (Stolt et al., 2002,2003, 2004). More recently, simultaneous deletion ofSox9 and Sox10 revealed a joint function in the mainte-nance of PDGFRa1 oligodendrocyte progenitor cells(Finzsch et al., 2008), which underscores the importanceof multiplicity of progenitor function of Sox9. SoxDfamily members Sox5and Sox6 are now known to mod-ulate SoxEprotein function in oligodendrocyte develop-ment by preventing precocious oligodendrocyte specifi-cation (Stolt et al., 2006).

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During skeletogenesis, cartilage and bone progeni-tors arise from a common precursor, which is specifiedby Sox9 (Akiyama et al., 2004, 2005). Osteoblast andchondrocyte development are mutually exclusive events:Wnt/beta-catenin signaling determines fate decisionsbetween osteoblast and chondrocyte lineages (de Crom-brugghe et al., 2001; Day et al., 2005; Hill et al., 2005).Sox8 expression is down-regulated upon differentiationof osteoblasts; it specifically prevents untimely osteoblastmaturation (Schmidt et al., 2005) and premature expres-sion of the run-related transcription factor 2 (Runx2), amaster regulator of osteoblast differentiation and boneformation. Sox9 inhibits osteoblast development andosteoblast developmental regulators such as beta-catenin(Day et al., 2005), and overexpression ofSox9drives car-tilage formation, a process that is mimicked by beta-cate-nin deletion. The reverse is also observed (Akiyamaet al., 2004). Furthermore, the commitment of progeni-tors to produce cartilage by the process of chondrogenesisis also effected through Sox9 by activating extracellularmatrix genes aggrecan, Col11a2, and Col2a1 (Bridgewateret al., 1998; Sekiya et al., 2000; Kawakami et al., 2005).Interestingly, the recruitment of Sox9 to the aggrecangene enhancer element is itself facilitated by SoxDmem-bers L-Sox5and Sox6(Han and Lefebvre, 2008).

In promoting chondrogenesis, Sox9 induces cellcycle arrest or exit and reduces the levels of the mito-gen-activated protein kinase ERK1 (Panda et al., 2001),whose inhibition had previously been found to promotechondrogenesis (Chang et al., 1998). Mechanistically,LEF/TCF transcription factors, which are beta-catenincoactivators, bind the same domain of beta-catenin asdoes Sox9. The binding of beta-catenin by Sox9 pre-vents LEF/TCF binding, inhibiting the expression ofWnt target genes. Interaction with beta-catenin couldalso inhibit the transactivating functions ofSox9, leadingto the eventual degradation of the Sox9/beta-catenincomplex. In addition to beta-catenin, Sox9also repressesRunx2 function in osteoblasts (Zhou et al., 2006). Theloss ofSox9derepresses the expression ofRunx1, Runx2,and Runx3 as well as target genes of Runx2 such asCol10a1, indicating that Sox9-Runx2 antagonism regu-lates skeletal fate determination.

In the intestinal epithelium, Sox9ablation results inincreased cell proliferation and hyperplasia (Bastide et al.,2007). The hyperplastic crypts of the Sox9-deficientintestine were found to overexpress Wntpathway-related

genes, such as c-Myc and cyclin D1, as well as increasethe number of cells expressing these genes. Direct inter-action between Sox9 and beta-catenin could not bedemonstrated by coimmunoprecipitation in this study;however, a mutated DNA binding domain of Sox9ablated the ability of Sox9 to modify beta-catenin-TCFactivity. Interestingly, when the transactivating and beta-catenin interacting domains of Sox9 were replaced witha VP16 transactivating domain, inhibition of beta-cate-nin-TCF activity surpassed that of the native Sox9. Thisobservation indicated that the action of Sox9 on beta-catenin function is likely to be mediated by the induced

expression of an inhibitor of beta-catenin-TCF (Bastideet al., 2007), which would agree well with the findingsthat many Sox proteins of different classes, which lackhomology outside of their HMG domains, possess theconserved property of inhibiting beta-catenin activity.

In myogenesis, Sox8 and Sox9 inhibit the MyoD-induced conversion of C3H 10T1/2 cells into myoblastsand repress the expression of myogenin by MyoD. Thissupports the notion that Sox8 and Sox9 are responsiblefor maintaining myoblasts in an undifferentiated state toprevent precocious differentiation into myotubes(Schmidt et al., 2003).

In all three systems of melanocyte, oligodendro-cyte, and chondrocyte development, SoxD and SoxEproteins are coexpressed. Whereas Sox5 and Sox6 costi-mulate Sox9 target genes in chondrocytes (Han and Le-febvre, 2008), Sox5 was recently shown to repress thetranscriptional activity of Sox10 during melanocyte de-velopment from the neural crest (Stolt et al., 2008) bybinding to Sox10 response elements in melanocytic tar-get genes, Mitf and Dct, in which multiple binding sitesforSox10have been mapped.

In the oligodendrocyte lineage, Sox5 and Sox6 arecoexpressed withSox10 in progenitor cells that have not

yet begun to express MBP, and ablation of Sox5 andSox6 results in precocious specification of ventricularzone cells to oligodendrocyte progenitor cells (Stoltet al., 2006). Both SoxDproteins repress terminal differ-entiation of oligodendrocytes by interfering with SoxE-dependent stimulation of myelin gene expression (Stoltet al., 2006), so that binding of either class of protein toknown Sox10-responsive elements in vitro was found ingel-shift assays to be mutually exclusive. With chromatinimmunoprecipitation, however, both Sox6 and Sox10were found at the Sox10-responsive MBP promoter atE16.5, but only Sox10was present on these sites in post-natal spinal cord (Stolt et al., 2006). It would appearthat, in myelin regulation, the nature of repression bySoxDincludes competition for interacting proteins, inso-far as both Sox5 and Sox6 interacted with Olig2 andNeurogenin 2 in GST-pulldown assays. These observa-tions attest to the mode of SoxD protein activity: repres-sion by competition for DNA or coactivator binding, orselective recruitment of corepressors at specific pro-moters. The last possibility is believed to be the likelymechanism for Sox5 in the neural crest (Stolt et al.,2008). Indeed, Sox9promotes Sox10expression in Neu-

ro2A cells, and coexpression of eitherSox5orSox6withSox9 ablated Sox9-dependent Sox10 expression (Stoltet al., 2003), indicating that Sox5 and Sox6could inter-fere with the ability ofSox9 to regulate the Sox10 pro-moter. The precise mechanisms regarding Sox9-depend-ent Sox10expression await elucidation.

SoxF(Sox7, Sox17, Sox18)

This group has been shown to be critical for endo-derm and hair development (Kanai-Azuma et al., 2002;Irrthum et al., 2003), cardiogenesis (Liu et al., 2007),




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and angiogenesis (Matsui et al., 2006; Young et al.,2006). The gene targets of SoxF proteins identified todate, such as FoxA and HNF1beta (Sinner et al., 2004),laminin alpha1 (Niimi et al., 2004), VCAM1 (Matsuiet al., 2006), and FGF-3 (Sinner et al., 2004) are de-pendent on their transactivation functions, and few spe-cific repressed targets have been described. In respiratoryepithelial cells, Sox17 promotes transdifferentiation ofalveolar type II cells into epithelial cells and stimulatespromoter activities of mFoxj1 while repressing those ofmSftpc, an alveolus-specific gene (Park et al., 2006).However, repression of gene expression by Sox17 mayalso be indirect. In the endoderm, Sox17 induces theexpression of a zinc-finger protein, Zfp202, whichrepresses the expression of the transcription factor

HNF4a (Patterson et al., 2008); thus gene targets ofSox17 transactivation have turned out to be transcrip-tional repressors themselves. Currently, the best estab-lished mechanism of repression by SoxF proteins is theinterference of Wnt signaling, as is frequently observedwith Sox proteins of other subfamilies. In the endoderm,Sox17 cooperates with beta-catenin to induce endoder-mal genes, and there is a shared sequence motif betweenSox17 and Sox7 that mediates the physical interactionbetween beta-catenin and Sox17 (Sinner et al., 2004).Deletion of this motif abolished binding to beta-cateninand partially reduced beta-catenin-mediated transcrip-

tional activity in lung cancer cells (Guo et al., 2008).The Sox7promoter was found to be hypermethylated inprostate cancer cell lines and colorectal cancers, anddemethylation of the Sox7 promoter resulted in a dra-matic increase in Sox7 expression. Ectopic expression ofSox7 in Sox7-null cells inhibited the proliferation of co-lon cancer cells, indicating that Sox7 inactivation isinvolved in cell proliferation and tumor progression(Guo et al., 2008). Sox17 interacts with both TCF andbeta-catenin (Sinner et al., 2007), and both domainson Sox17 are required to antagonize Wnt signaling bypromoting their proteasomal degradation.

Dual roles for Sox17 in promoting cell cycle exitand progenitor maturation were also revealed in the oli-godendrocyte lineage, where reduced progenitor cell

proliferation and increased morphological differentiationwere simultaneously induced by the overexpression ofSox17 (Sohn et al., 2006). Understanding Wnt pathwaymodulation by Sox proteins could help to demystify thecomplex relationship between cell cycle control and lin-eage progression. The ability of SoxF members to regu-late Wnt pathway signaling was further highlighted in arecent study comparing the repression of beta-catenin/TCF activity by various Sox family members (Sinneret al., 2007). Both Sox10 and Sox17 are potent inhibi-tors of beta-catenin-mediated transcription (Sinner et al.,2007) and are activators of myelin gene expression in the

TABLE I. Activator Functions of Sox Proteins

Family Function References

SoxB1 SoxB1 members activate differentiation of telencephalic precursors into neurons Ekonomou et al., 2005

Sox1 enhances neurogenin expression Kan et al., 2004

Sox2 activates cyclinD1 expression with b-catenin in breast cancer Chen et al., 2008

Sox1 and Sox2 activate crystallin genes Uchikawa et al., 1999SoxC Sox4 and Sox11 induce neuronal phenotype, and activate neuronal class IIIb-tubulin

(Tubb3) gene promoter

Bergsland et al., 2006

Sox4 supports glucokinase expression Goldsworthy et al., 2008

Sox4 enhances b-catenin signaling Sinner et al., 2007

SoxD Sox5 recruits coactivators to Sox9target genes Hattori et al., 2008

Sox5and Sox6costimulate Sox9target genes in chondrocytes Han and Lefebvre, 2008

SoxE Promote neural crest multipotentiality Kim et al., 2003

Promote glial development of neural crest progenitor cells Britsch et al., 2001

Sox9 promotes progenitor commitment, promotes expression ofAggrecan, Col11a2,

Col2a1

Bridgewater et al., 1998; Sekiya et al.,

2000; Kawakami et al., 2005

Sox9promotes Sox10expression in Neuro2A cells Stolt et al., 2003

Sox9and Sox10maintain PDGFRalpha1 cells Finzsch et al., 2008

SoxF Promote FoxA and HNF1beta expression Sinner et al., 2004

Promote laminin alpha 1 expression Niimi et al., 2004

Promote VCAM1 expression Matsui et al., 2006

Promote FGF-3 expression Sinner et al., 2004

Promote endoderm development Kanai-Azuma et al., 2002

Promote hair development Irrthum et al., 2003

Promote cardiogenesis Liu et al., 2007

Promote angiogenesis Young et al., 2006

Promote transdifferentiation to epithelial cells Park et al., 2006

Stimulate activity ofmFoxj1 promoter Park et al., 2006

Sox17 induces expression ofZfp202 zinc finger protein Patterson et al., 2008

Sox17and Sox7coactivate b-catenin target genes in endoderm Sinner et al., 2004

Sox17promotes myelin gene expression Sohn et al., 2006

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oligodendrocyte lineage (Stolt et al., 2002; Sohn et al.,2006), whereas members of SoxC (Sox4 and -11) werepotent activators of Wnt signaling (Sinner et al., 2007),with Sox4 recently shown to be an inhibitor of oligo-

dendrocyte maturation (Potzner et al., 2007). The activ-ities of Sox proteins as activators and repressors aresummarized in Tables I and II.

Sox TRANSCRIPTION FACTORSAND DISEASE

Sox factor expression and function are modified ina variety of tumors and neurological disorders. Here wediscuss recent findings that suggest a role for these pro-teins in the formation and maintenance of some braintumors. Sox2 expression was analyzed in different types

of brain tumors, based on the hypothesis that cancerstem cells are responsible for their propagation (Phiet al., 2008). Sox2 was expressed in a variety of glialtumors of astroglial, oligodendroglial, and ependymal lin-

eages. Sox2 was also found in tumors of embryonal ori-gin (supratentorial primitive neuroectodermal tumors)but not in medulloblastomas and pineoblastomas.Because most of the Sox2-expressing cells in the tumorscoexpressed GFAP, and Sox2-negative cells in medullo-blastomas and pineoblastomas expressed neuronalmarkers, it was concluded that Sox2 might be a markerof tumors of glial lineages (Phi et al., 2008). Conversely,heterozygous loss-of-function mutations in SOX2 causesanophthalmia, microphthalmia, and coloboma. Thesepatients often present with extraocular abnormalities,such as learning disability, seizures, motor dysfunction,

TABLE II. Repressor Functions of Sox Proteins

Family Function References

SoxB1 Repress neuronal differentiation and maintain progenitor-specific expression Bylund et al., 2003; Graham et al.,

2003; Holmberg et al., 2008

Bind b-catenin and inhibits b-catenin signaling Kan et al., 2004

SoxB2 Inhibit activation of delta-crystallin DC5enhancer Sandberg et al., 2005Counteract activities ofSoxB1 to promote neurogenesis Sandberg et al., 2005

SoxC Sox4 represses oligodendrocyte development Potzner et al., 2007

Sox11 represses oligodendrocyte development He et al., 2007

SoxD Sox5 prevents premature development of neurons Lai et al., 2008

Sox5represses SPARC Huang et al., 2008

Sox5and Sox6 repress IHH signaling, FGFR3 and Runx2 Smits et al., 2004

Sox5represses Sox10targets Mitf and Dct Stolt et al., 2008

Sox5and Sox6 suppress premature oligodendrocyte generation. Sox6 corecruited to Sox10

site on MBPpromoter at E16.5

Stolt et al., 2006

Sox5and Sox6repress Sox9-induced Sox10expression in Neuro2A Stolt et al., 2006

Sox5and Sox6 interact with Olig2 and neurogenin 2 Stolt et al., 2006

Sox6 represses Ca21 alpha1c promoter Cohen-Barak et al., 2003

Sox6represses epsilon globin expression Yi et al., 2006

Sox6represses insulin II gene expression Iguchi et al., 2005

Sox6suppresses cyclin D1 promoter activity Iguchi et al., 2007

Sox13 suppresses alphaBeta T-lymphocyte differentiation Melichar et al., 2007

Sox13 antagonizes TCF1 function and cell proliferation Melichar et al., 2007

SoxE Sox8 prevents premature osteoblast maturation Schmidt et al., 2005

Sox9 suppresses neuronal markers Pax6, Pax7, Nkx6, Irx3 Cheung and Briscoe, 2003

Sox8and Sox9prevent precocious myotube differentiation Schmidt et al., 2003

Sox10overcomes BMP2 and TGFbeta signaling to maintain gliogenic potential Kim et al., 2003

Sox10prevents Schwannoma from differentiating into myofibroblast s R oh et al., 2006

Sox9 inhibits osteoblast development de Crombrugghe et al., 2001; Hill

et al., 2005

Sox9 inhibits Wnt signaling inhibiting b-catenin transcriptional activity directly and by

affecting its stability

Akiyama et al., 2004; Topol et al.,

2009

Sox9reduces ERK1 levels Panda et al., 2001

Sox9 inhibits Runx2 function Zhou et al., 2006

Sox9suppresses proliferation in intestinal epithelium Bastide et al., 2007

Sox9suppresses generation of spinal cord motorneurons, V2 interneurons and astrocytes Stolt et al., 2002, 2003, 2004

Sox10 inhibits b-catenin-mediated transcription Sinner et al., 2007SoxF Repress mSftpcgene expression in alveolus Park et al., 2006

Sox17represses HNFa expression Patterson et al., 2008

Sox7 inhibits cell proliferation in colon cancer Guo et al., 2008

Sox17antagonizes Wntsignaling Sinner et al., 2007; Zorn et al.,

1999

Sox17represses cell proliferation in oligodendrocyte progenitor cells Sohn et al., 2006




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and postnatal growth failure (Ragge et al., 2005). Addi-tionally, a number of patients with SOX2 mutationsshow hypogonadotropic hypogonadism, with anteriorpituitary hypoplasia and gonadotropin deficiency (Tzia-feri et al., 2008), lending support to a multisystem func-tion of SOX2 in human development. Surveys of geneexpression in medulloblastomas have found an overex-pression of SOX4 and SOX11 (Lee et al., 2002; Yokotaet al., 2004), with strong nuclear staining in a majorityof these tumors (de Bont et al., 2008). SOX11 isexpressed in fetal progenitors (Weigle et al., 2005) andabsent from normal mature cerebellum (de Bont et al.,2008), so the expression of this marker suggests anembryonic origin of the tumor. SOX6 is expressed athigher levels in human gliomas and fetal brain than innormal adult tissue, and it is considered a potential diag-nostic marker for these tumors (Ueda et al., 2004). In anindependent study, SOX6 was found to be up-regulatedtogether with SOX8 and SOX13 in oligodendrogliomas(Schlierf et al., 2007). SOX10 is also ubiquitouslyexpressed in gliomas (Bannykh et al., 2006). Altogether,these findings are consistent with the hypothesis that gli-oma cells are less differentiated than normal adult glia.Interestingly, Sox genes were found to be up-regulatedin tumors of both oligodendroglial and astrocytic line-ages, consistent with the notion that gliomas might sharea common origin from stem cells or glial progenitors.This hypothesis has also been confirmed in pheochro-mocytomas, in which both Sox9 and Hey1genes thatare involved in the maintenance of a progenitor stateare highly expressed (Powers et al., 2007).

Different mutations in the SOX10 gene are associ-ated with two distinct groups of neurocristopathies: amilder form comprising Waardenburg syndrome (WS)and Hirschsprung disease (HSCR) and a more severetrait, peripheral demyelinating neuropathy, central dys-myelinating leukodystrophy, Waardenburg syndromeand Hirschsprung disease (PCWH). PCWH is character-ized by deficiencies in Schwann cells, oligodendrocytes,melanocytes, and enteric ganglia neurons (Inoue et al.,1999, 2002). WS and HSCR are autosomal dominantdisorders caused by cellular defects in the embryonicneural crest. WS and HSCR occur simultaneously inpatients with Waardenburg-Shah syndrome (WS4).Sox10 mutations were identified in families with WS4but not in patients with HSCR alone (Pingault et al.,1998). Importantly, these mutations are likely to cause

haploinsufficiency of the SOX10 protein. Analysis ofthese disease-causing SOX10mutations has revealed pre-mature terminating codons and a relationship betweenthe position of the mutation and the severity of disease(Inoue, 2004). Efforts to characterize the various mutantSox10proteins have demonstrated some dominant nega-tive properties (Inoue, 2004) but have been unable tofully explain the toxic effects of extending translationinto the 30 untranslated region (Inoue, 2007).

Recent studies point to a role ofSOX10 and oli-godendrocytes in the pathophysiology of schizophrenia.In patients with schizophrenia, the Sox10gene is highly

methylated in the CpG island of the sex-determiningregion Y-box, and its expression is significantlydecreased (Iwamoto et al., 2005). Importantly, the meth-

ylation status of Sox10 correlated with its reducedexpression and with modified expression of other oligo-dendrocyte genes. The CpG island of the oligodendro-cyte transcription factorOlig2 was rarely methylated, andthe methylation status of myelin basic protein was notassociated with changes in other oligodendrocyte geneexpression (Iwamoto et al., 2005). The authors of thestudy concluded that, in schizophrenia, Sox10 methyla-tion is likely to be an epigenetic indicator of oligoden-drocyte dysfunction.

CONCLUSIONS

It is apparent that oligodendrocyte dysfunctionfound in schizophrenia could be attributed to the acti-vating functions of Sox10, but, in many tumors, thesilencing function of Sox proteins on the proliferative

effects of Wnt signaling has been attenuated (Guo et al.,2008). Given the structural features of the known Soxgroups and the diversity of protein interactions docu-mented to date, the mechanism of target gene selectionby Sox proteins in specific cell types has become a sub-

ject of intense study. Current models indicate that thedynamic patterns of tissue-specific Sox gene expression,coupled with partner protein availability and selectivity,are mechanisms likely to underlie the specific changes ingene expression associated with fate decisions and impor-tant transitional phases in development (Kamachi et al.,2000). Selective DNA binding of promoters that areactivated by Sox proteins and their cofactors is enhancercontext-dependent (Kamachi et al., 1999), and it would

be reasonable to expect that transcriptional repression bySox proteins would be no less complex and more diffi-cult to predict, in that neither activation domains norDNA binding would be required. Elucidating mecha-nisms of target specificity in developmental regulation bySox proteins will be enhanced by continued efforts inthe identification and characterization of Sox proteinfunction.

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The Yin and Yang of Sox Proteins- Activation and Repression in Development and Disease

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