ErbB3Dependent Functions of Sox10

A systematic analysis of the expression of ErbB3 and Sox10 during embryonic development revealed both genes to be expressed in almost identical spatiotemporal patterns (Britsch et al. 2001). Both genes are expressed in neural crest cells immediately after their birth from the neuroepithelium of the dorsal neural tube. Coexpression of Sox10 and ErbB3 is sustained in primary derivatives of the neural crest, like dorsal root and cranial ganglia anlagen, the primordial sympathetic

Sox 10

HMG

TAD

Dom

HMG

1

Soxl0 MAEEQDLSEV2LSPVGSEEPRCLSPGSAPSLGPOGSGGGSGLBASPCPCE Dom MAEEQDL5 E WLSPVG5 EEPRCLSFG5AP5LGP DGGGGGSGL RA5FGPGE

50 50

So* 10 Dom

L G KVKK EQQ DG E AD DD KFPVCI REAV5QVLSGYCWTLVPKPVRVN GA3KS LGKVXKBQQDGE ADDDKFF./C IR EAVSQVLSGYEWTLVPKPVRVNGASXS

100 100

SoxlO Dom

KP HVKR PMHAFMVWAQAARHKLADOY PHI H HAS LS KTL GXISiRLLBB S KP^<RPMMA?m^AOAARaKTADQYPKLHilMT.SKTT.GKr,WRTJ-NiISDK

150 ISO

SoxlO Dom

RPF lEEAERLRiJQHKKDKPDYKYQPRRRKHGKAAQSE AECPGGEAEQGGA RPFIEEAERLRHOHKKDHPDYKYQPRRRKM(atAA53EAECPGQGSRARRG

200 200

Soxl0 AAIQAHYKSAHLDBRHPBECSPKSDGNPEHPSGQS HGPPTPPTTPKTELQ Dam CCYSGSLQECPPGPPAPRRRLPHVRWBPRAPLR PE PWPPXP5NKPKDRAA

250 250

SoxlO SGK^PKHDGRSLGEtWKpaiDFGIiVDIGElSliEVHSKJiSTFIA'TEliDQY 300

SoxlO Dam

LPPNGHPGHVGSYSAAGYGLGSALAVAS GHSAMIS KPPGVAL FTVSPPGV

350 292

SoxlO Dom

DAKAQVKTETTGPQGPPHYTDQPSTSgiAYTSLSLPKYGSAFPSISRPQF

400 2 92

SoxlO Dom

DYSDSgpSGPYYCHACQASCLYSAFS¥HCPSC«PLYTA1SDPSPSCPfiSH

292

SoxlO Dom b

SpTHWEaP/YTTLSRP

166 292

Fig. 12a,b a Schematic representation of the domain organization of wildtype Sox10 and the Sox10Dom protein (HMG, HMG-box DNA binding domain; TAD, transactivation domain). b Aminoacidsequences derivedfromthe Soxl Owildtypealleleandfrom theSoxl 0Dom allele. In the Sox10Dom allele a point mutation results in a frameshift at aa position 194 and the generation of a truncated protein, which lacks its transactivation domain. HMG-box and truncated part of the mutant protein are highlighted in red and green, respectively

Fig. 12a,b a Schematic representation of the domain organization of wildtype Sox10 and the Sox10Dom protein (HMG, HMG-box DNA binding domain; TAD, transactivation domain). b Aminoacidsequences derivedfromthe Soxl Owildtypealleleandfrom theSoxl 0Dom allele. In the Sox10Dom allele a point mutation results in a frameshift at aa position 194 and the generation of a truncated protein, which lacks its transactivation domain. HMG-box and truncated part of the mutant protein are highlighted in red and green, respectively nervous system, and vagal neural crest cells, which enter the primitive intestine and contribute to the developing enteric nervous system (Fig. 11). Both genes, however, possess nonoverlapping expression domains. ErbB3 but not Sox10 is expressed in the myotome, whereas Sox10 but not ErbB3 is expressed in the melanocytic lineage (Britsch et al. 2001). Together, these findings suggested that both genes interact genetically. Analysis of Sox10 and ErbB3 expression in homozygous ErbB3 and Dom mutant mice, respectively, demonstrated that ErbB3 expression in neural crest cells depends on Sox10 function (Britsch et al. 2001). In homozygous Dom mutants, no ErbB3 gene expression is detectable in migrating trunk neural crest cells nor in those crest cells that have colonized their primary targets on both sides of the neural tube, the dorsal aorta, or along outgrowing spinal nerves (Fig. 11). The ErbB3 gene is transiently expressed independently of

Sox10 in newly generated neural crest cells during earlier developmental stages, but these cells require Sox10 function to maintain ErbB3 gene expression immediately after they have started to migrate away from their origins (Britsch et al. 2001). This is supported by the in vitro observation that Sox10 can increase ErbB3 expression in N2A cells (Britsch et al. 2001). It is unclear whether the interaction of Sox10 and the ErbB3 gene is direct or indirect, and no Sox10 responsive element has been identified in the genomic locus of ErbB3. However, the rapid induction of ErbB3 by Sox10 in cell culture argues in favor of a direct interaction. Recent experimental data have shown that individual HMG domains of Sox proteins are similar to each other in their sequence preference and DNA binding activity, indicating that binding to a specific target must be determined by additional mechanisms, as for example flanking DNA sequences, and multiprotein complexes (Kamachi et al. 2000; Mollaaghababa and Pavan 2003). In the case of the P0 gene, which encodes a myelin-associated glycoprotein, and which has been shown to be a direct Sox10 target, flanking DNA sequences and the binding of Sox10 as a dimer are critical for the interaction of Sox10 with its specific target (Peirano et al. 2000; Peirano and Wegner 2000). The tyrosine kinase receptor c-ret is essential for the survival of neural crest cells that enter the intestine and contribute to the development of the enteric nervous system (Schuchardt et al. 1994; Schuchardt et al. 1995; Durbec et al. 1996). Mice with mutations of both the Sox10 and the c-ret gene develop a megacolon due to the apoptotic loss of enteric ganglia (Schuchardt et al. 1994; Durbec et al. 1996; Herbarth et al. 1998; Southard-Smith et al. 1998; Kapur 1999; Southard-Smith et al. 1999). Intriguingly, Sox10 has been shown to control expression of c-ret in enteric neural crest cells by direct protein-protein interaction with an additional transcription factor, Pax3, that binds to the c-ret gene in the close vicinity of the Sox10 binding site (Lang et al. 2000; Lang and Epstein 2003). The requirement of a partner factor in order to exert transcriptional regulation of a given target gene has been demonstrated for several other Sox proteins (Kamachi et al. 2000). It is tempting to speculate that in the case of the regulation of ErbB3 expression by Sox10, additional proteins, yet to be determined, are also involved.

Since Sox10 mutant animals lack ErbB3 expression in neural crest cells, both Sox10 and ErbB3 mutant mice show very similar defects in neural crest cell development. Both mutants have an impaired development of cranial ganglia, a severe hypoplasia of the trunk sympathetic nervous system, and reduced numbers of Schwann cell precursors along outgrowing spinal nerves (Erickson et al. 1997; Riethmacher et al. 1997; Britsch et al. 1998; Britsch et al. 2001). Interestingly, migration of neural crest cellshas been describedtobelessseverelyaffectedinSox10 mutants, which is most likely due to the short period of expression of ErbB3 independently of Sox10 function in newly generated neural crest cells (Britsch et al. 2001).

In addition to ErbB3-dependent developmental functions of Sox10, this transcription factor has been shown to execute ErbB3-independent developmental functions. In homozygous Dom mutants, development of the enteric nervous system and of the melanocytic lineage are severely affected; however, their development is unaffected in ErbB3 mutant mice.

Moreover, Sox10 has been demonstrated to play an ErbB3-independent key role in the development of the peripheral glial cell lineage (Britsch et al. 2001).

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