Sox10 mutation disrupts neural crest development in DOM Hirschsprung mouse model
Sox10 mutation disrupts neural crest development in DOM Hirschsprung mouse model
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DOI：
10.1038/ng0198-60
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发表时间：
1998-01-01
期刊：
影响因子：
30.8
通讯作者：
Pavan, WJ
中科院分区：
文献类型：
--
作者：
Southard-Smith, EM;Kos, L;Pavan, WJ
先天性巨结肠（HSCR，MIM #142623）是一种多基因神经嵴病（神经嵴疾病），其特征是远端结肠的可变部分缺乏肠神经节。HSCR个体的亚组也存在神经嵴来源的黑素细胞缺陷（Hirschsprung-Waardenburg，HSCR-WS，MIM #277580）。小鼠模型在HSCR疾病基因的鉴定和分析中起着重要作用。这些包括内皮素B受体（Ednr B（s-1）;参考文献1，2）、内皮素3（Edn 3（ls）;参考文献1，3）、酪氨酸激酶受体cRet（4）和神经胶质源性神经营养因子（5-7）缺陷的小鼠。杰克逊实验室自发产生了另一种HSCR疾病小鼠模型Dom（8）。虽然Dom/+杂合子小鼠显示远端结肠中神经嵴衍生的肠神经节的区域缺陷，但Dom/Dom纯合子动物是胚胎致死的（8）。我们已经确定，过早终止Sox 10，SRY样HMG盒家族的转录因子的成员，是负责在Dom小鼠的神经嵴衍生物的情况下。我们证明了Sox 10在正常神经嵴细胞中的表达，破坏了Sox 10和HSCR疾病基因Ednrb在Dom突变胚胎中的表达，以及由于细胞凋亡导致的神经嵴衍生物的损失。我们的研究表明，Sox 10对周围神经系统的正常发育至关重要。我们建议SOX 10作为HSCR患者的候选疾病基因，其疾病没有确定的遗传起源。
Hirschsprung disease (HSCR, MIM #142623) is a multigenic neurocristopathy (neural crest disorder) characterized by absence of enteric ganglia in a variable portion of the distal colon. Subsets of HSCR individuals also present with neural crest-derived melanocyte deficiencies (Hirschsprung-Waardenburg, HSCR-WS, MIM #277580). Murine models have been instrumental in the identification and analysis of HSCR disease genes. These include mice with deficiencies of endothelin B receptor (Ednrb(s-l); refs 1,2) endothelin 3 (Edn3(ls); refs 1,3) the tyrosine kinase receptor cRet(4) and glial-derived neurotrophic factor(5-7). Another mouse model of HSCR disease, Dom, arose spontaneously at the Jackson Laboratory(8). While Dom/+ heterozygous mice display regional deficiencies of neural crest-derived enteric ganglia in the distal colon, Dom/Dom homozygous animals are embryonic lethal(8). We have determined that premature termination of Sox10, a member of the SRY-like HMG box family of transcription factors, is responsible for absence of the neural crest derivatives in Dom mice. We demonstrate expression of Sox10 in normal neural crest cells, disrupted expression of both Sox10 and the HSCR disease gene Ednrb in Dom mutant embryos, and loss of neural crest derivatives due to apoptosis. Our studies suggest that Sox10 is essential for proper peripheral nervous system development. We propose SOX10 as a candidate disease gene for individuals with HSCR whose disease does not have an identified genetic origin.