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 ganglia in the colon and can be associated with deafness. Homozygous animals die in utero and there are 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 caused 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 semidominant in nature. We have made transgenic mice that overexpress Sox10 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 heirarchical 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 completely replace 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 human diseases for mutations in these genes. We have extended the screen to look for earlier embryonic neural crest defects and have mapped and cloned several mutants which are candidates for human diseases. We are sequencing DNA from individuals with relevant diseases to determine if orthologous genes are mutated. In addition we have sequenced non-coding DNA from multiple samples of HSCR disease and are looking for correlations of sequence variants disease severity. We have established a collaboration with HSCR disease scientists to examine the microbiome alterations associated with changes in disease state.
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