ANALYSIS OF DOMINANT MEGACOLON--ANOTHER MODEL FORHIRSCHS

SOX10转录因子突变的杂合动物在神经嵴发育中表现出多种缺陷，包括皮肤中黑色素细胞数量减少，结肠中肌肠神经节缺失，并可能与耳聋有关。异种动物在子宫内死亡，整个周围神经系统存在广泛的缺陷。巨结肠病是一种人类先天性疾病，也表现为直肠结肠神经节病，可与色素沉着减退有关，由SOX10突变引起。因此，SOX10小鼠以及其他神经嵴突变小鼠可作为该疾病的小鼠模型。我们发现SOX10缺陷破坏了早期神经嵴基因、MITF、DCT和EDNRB的表达，将SOX10基因置于神经嵴发育通路的早期。我们正在使用额外的标记和谱系定向基因转移来确定SOX10的作用模式及其对下游靶标的影响。探讨SOX10在巨结肠疾病和其他神经嵴相关疾病中的作用。我们已经证明SOX10直接控制MITF和DCT的表达。我们已经证明，对目标基因的影响在自然界中是半显性的。我们已经建立了一个向神经嵴干细胞添加基因的系统，以弥补遗传缺陷。我们将使用该系统来测试SOX10与其靶基因之间的等级关系。

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.