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MIT 7 72 - SoxE Factors Function Equivalently

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SoxE Factors Function Equivalently during Neural Crest and Inner Ear Development and Their Activity Is Regulated by SUMOylationIntroductionResultsSox9 and Sox10 Have Equivalent Effects on Neural Crest FormationSox9 and Sox10 Promote Melanocyte and Glial Formation and Inhibit Neuronal DifferentiationSox9 Can Rescue Neural Crest Formation in Sox10-Depleted EmbryosSox9 and Sox10 Direct the Formation of Enlarged and Ectopic Otic VesiclesUBC9 and SUMO-1 Are SoxE-Interacting FactorsSUMOylation Modulates SoxE Function during Neural Crest DevelopmentSUMOylation of SoxE Proteins Is Important for Inner Ear DevelopmentDiscussionExperimental ProceduresDNA Constructs and Embryo MethodsYeast Two-Hybrid AssaysWestern Blots and SUMOylation AssaysMorpholino Oligonucleotide Rescue ExperimentsSupplemental DataAcknowledgmentsReferencesDevelopmental Cell, Vol. 9, 593–603, November, 2005, Copyright ©2005 by Elsevier Inc. DOI 10.1016/j.devcel.2005.09.016SoxE Factors Function Equivalentlyduring Neural Crest and Inner Ear Developmentand Their Activity Is Regulated by SUMOylationKimberly M. Taylor and Carole LaBonne*Department of Biochemistry, Molecular Biology,and Cell Biology andRobert H. Lurie Comprehensive Cancer CenterNorthwestern UniversityEvanston, Illinois 60208SummarySox9 and the closely related factor Sox10 are essen-tial for the formation of neural crest precursor cells,and play divergent roles in the process by whichthese cells are subsequently directed to form specificderivatives. These group E Sox factors have alsobeen implicated in the development of the vertebrateinner ear. Despite their importance, however, themechanisms that allow SoxE proteins to regulatesuch a diverse range of cell types have remainedpoorly understood. Here we demonstrate that duringvertebrate development, the activities of individualSoxE factors are well conserved and are regulatedby SUMOylation. We show that SoxE mutants thatcannot be SUMOylated, or that mimic constitutiveSUMOylation, are each able to mediate a subset ofthe diverse activities characteristic of wild-type SoxEproteins. These findings provide important mecha-nistic insight into how the activity of widely deployeddevelopmental regulatory proteins can be directed tospecific developmental events.IntroductionSox proteins are high mobility group (HMG) family tran-scription factors that regulate diverse developmentalprocesses (Wegner, 1999). The Sox family is dividedinto subgroups A–J that possess highly homologousHMG-type DNA binding domains but share little overallhomology outside of this region (Bowles et al., 2000).All Sox proteins possess transcriptional activation do-mains; however, they bind DNA with low affinity, andare thought to require DNA binding cofactors to stabi-lize their interactions with DNA (Kamachi et al., 2000).Several reports have now identified partner proteinsthat can interact with Sox family members in order tosynergistically activate transcription (Bondurand et al.,2000; Lang and Epstein, 2003). Members of Sox groupE, comprised of Sox8, Sox9, and Sox10, are furthercharacterized by the presence of two conserved re-gions (termed E1 and E2) that have been proposed tobe protein-protein interaction domains (Bowles et al.,2000).SoxE factors have emerged as important regulatorsof the neural crest, a population of migratory, tissue-invasive stem cells that plays a central role in the devel-opment of the vertebrate body plan. Neural crest cellsmigrate extensively, populate diverse regions through-*Correspondence: [email protected] the embryo, and give rise to a wide range of deriva-tives that includes most of the neurons and glia of theperipheral nervous system (PNS), melanocytes, andcraniofacial cartilage. At neural plate stages, Sox9 andSox10 are expressed by all neural crest precursor cells,although the expression of Sox9 precedes that of Sox10(Aoki et al., 2003; Lee et al., 2004). Later, expression ofthese two factors in neural crest derivatives becomesnonoverlapping, with Sox9 expression maintained incells contributing to facial cartilage and Sox10 expres-sion restricted to presumptive melanoblasts and glia(Spokony et al., 2002; Aoki et al., 2003; see Figure S1in the Supplemental Data available with this article on-line). In vivo, Sox9 and Sox10 likely play divergent rolesin the transcriptional control of these different fates(Southard-Smith et al., 1998; Britsch et al., 2001; Stoltet al., 2002); however, the extent to which this is due toany distinct activities possessed by these factors hasremained unclear.In Xenopus, morpholino-mediated depletion of eitherSox9 or Sox10 leads to a loss of neural crest precursorformation, while overexpression of Sox9 or Sox10 canlead to expansion of the neural crest progenitor domain(Spokony et al., 2002; Aoki et al., 2003; Honore et al.,2003). Thus, by the criteria of their effects on neuralcrest precursor formation, these two closely relatedSoxE factors appear to have similar activities. However,it has been reported that overexpression of Sox10 butnot Sox9 induces melanocyte formation (Aoki et al.,2003), indicating that each of these factors may alsopossess some distinct activities. Studies using a num-ber of model organisms have also implicated SoxE fac-tors in inner ear development (Watanabe et al., 2000;Liu et al., 2003; Saint-Germain et al., 2004). In Xenopus,Sox9 is the earliest marker of the newly induced oticplacode, which will give rise to the inner ear, and mor-pholino-mediated depletion of Sox9 leads to a failureof inner ear formation (Saint-Germain et al., 2004). Theeffects of upregulating SoxE activity on inner ear devel-opment have yet to be reported.Given their overlapping expression patterns and pro-posed roles in neural crest precursor formation, neuralcrest lineage diversification, and otic placode forma-tion, it seemed possible that individual SoxE factorsmight possess some divergent activities, and that thecomplement of SoxE factors expressed in a cell mightplay an instructive role in dictating that cell’s fate. Totest this hypothesis, we expressed Sox9 or Sox10 inearly Xenopus embryos and compared and contrastedtheir activities. We found that each factor could directthe formation of neural crest precursors and the devel-opment of a range of neural crest derivatives, and wedetected no differences in the activities of Sox9 andSox10 in these assays. Moreover, we found that misex-pression of Sox9 or Sox10 frequently resulted in theformation of enlarged or ectopic


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