ANALYSIS OF DOMINANT MEGACOLON--ANOTHER MODEL FORHIRSCHS

SOX 10转录因子突变体杂合的动物在神经嵴发育中表现出多种缺陷，包括皮肤中黑素细胞数量减少、结肠中肌间神经节缺失，并且可能与耳聋相关。同型动物在子宫内死亡，整个外周神经系统存在广泛的缺陷。作为一种人类先天性疾病，先天性巨结肠症也表现为直肠结肠性无神经节细胞症，并可能与色素减退有关，并由SOX 10突变引起。因此，SOX 10小鼠以及其他神经嵴突变小鼠可作为该疾病的小鼠模型。我们已经发现，SOX 10缺陷破坏了早期神经嵴基因的表达，MITF、DCT和EDNRB将SOX 10基因置于神经嵴发育途径的早期。我们正在使用额外的标记物和谱系定向基因转移来确定SOX 10的作用模式及其对下游靶点的影响。SOX 10在先天性巨结肠和其他神经嵴相关疾病中的作用将被探讨，我们已经证明SOX 10直接控制MITF和DCT的表达。我们已经表明，对靶基因的影响是semondomnant的性质。我们已经建立了一个系统，将基因添加回神经嵴干细胞，以弥补遗传缺陷。我们将使用这个系统来测试SOX 10和它的靶基因之间的层次关系。

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 semondomnant in nature. We have established a system for adding genes back to neural crest stem cells in order to complement genetic defects. We will use this system to test hierarchial relationships between SOX10 and its target genes.