Animals heterozygous for mutants in the SOX10 transcription factor exhibit multiple defects in neural crest development including reduced numbers of melanocytes in the skin, an absence of myenteric ganglion in the colon and can be associated with deafness. Homozgous animals die in utero and there is extensive defects in the entire peripheral nervous system. A human congenital disorder, Hirschsprung disease also exhibits rectocolic aganglionosis and can be associated with hypopigmentation and casued by SOX10 mutations. Thus SOX10 mice, as well as the other neural crest mutant mice, serve as mouse models for this disease. We have found that the SOX10 defects disrupt expression of early neural crest genes, MITF, DCT and EDNRB placing the SOX10 gene early in the neural crest development pathway. We are using additional markers and lineage directed gene transfer to determine the mode of action of SOX10 and its effects on downstream targets. Investigation of the involvement of SOX10 in Hirschsprung disease and other neural crest related disorders will be explored.We have demonstrated that SOX10 directly controls the expression of MITF and DCT. We have shown that the effect on target genes is semindomnant in nature. We have made transgenic mice that overexpress Sxo10 to analyze its effects on neural crest stem cell development. We have also established a system for adding genes back to neural crest stem cells in order to complement genetic defects. We used this system to test hierarchial relationships between SOX10 and its target genes. We have demonstrated that we can use this system to correct SOX10 defects in vitro. We have generated vectors to make this very efficient. We have shown that MITF is not sufficient to complete repalce SOX10 in development. We have also established a whole genome mutagenesis program to identifying SOX10 genetic interaction factors. We have identified 7 heritable loci, mapped five and cloned the mutation in four of the genes. These may become human modifier loci and interesting contributors to neural crest developmental pathways. We are testing humand diseases for mutations in these genes. We have extended the screen to look for earlier embryonic neural crest defects and have mapped four mutants and cloned the gene for three. In addition we have sequenced non-coding DNA from multiple samples of HSCR disease and are looking for correlations of sequence variants disease severity.

Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2009
Total Cost
$1,004,214
Indirect Cost
Name
National Human Genome Research Institute
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Cronin, Julia C; Loftus, Stacie K; Baxter, Laura L et al. (2018) Identification and functional analysis of SOX10 phosphorylation sites in melanoma. PLoS One 13:e0190834
Ruiz, Rolando; Jahid, Sohail; Harris, Melissa et al. (2017) The RhoJ-BAD signaling network: An Achilles' heel for BRAF mutant melanomas. PLoS Genet 13:e1006913
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Watkins-Chow, Dawn E; Cooke, Joanna; Pidsley, Ruth et al. (2015) Correction: Mutation of the Diamond-Blackfan Anemia Gene Rps7 in Mouse Results in Morphological and Neuroanatomical Phenotypes. PLoS Genet 11:e1005682
Saldana-Caboverde, Amy; Perera, Erasmo M; Watkins-Chow, Dawn E et al. (2015) The transcription factors Ets1 and Sox10 interact during murine melanocyte development. Dev Biol 407:300-12
Hwang, Hun-Way; Baxter, Laura L; Loftus, Stacie K et al. (2014) Distinct microRNA expression signatures are associated with melanoma subtypes and are regulated by HIF1A. Pigment Cell Melanoma Res 27:777-87
Harmacek, Laura; Watkins-Chow, Dawn E; Chen, Jianfu et al. (2014) A unique missense allele of BAF155, a core BAF chromatin remodeling complex protein, causes neural tube closure defects in mice. Dev Neurobiol 74:483-97

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