Identification of Sox8 as a modifier gene in a mouse model of Hirschsprung disease reveals underlying molecular defect
Identification of Sox8 as a modifier gene in a mouse model of Hirschsprung disease reveals underlying molecular defect
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DOI：
10.1016/j.ydbio.2004.09.014
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发表时间：
2005-01-01
影响因子：
2.7
通讯作者：
Wegner, M
中科院分区：
文献类型：
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作者：
Maka, M;Stolt, CC;Wegner, M
在Sox10基因中携带杂合突变的小鼠显示结肠无神经节细胞症，并代表人类先天性巨结肠病的模型。在这里，我们表明，密切相关的Sox8功能作为Sox10依赖性肠神经系统缺陷的修饰基因，因为它增加了Sox10杂合子小鼠的缺陷的发生率和严重程度，尽管对肠神经系统发育本身没有可检测到的影响。Sox 8表现出与Sox 10非常相似的表达模式，在迷走神经和肠神经嵴细胞中发生，随后局限于肠神经胶质。在Sox10杂合子小鼠中Sox8等位基因的缺失损害了肠神经嵴细胞在肠道的早期定殖。而增殖，细胞凋亡和神经元分化是正常的肠神经嵴细胞在肠道的突变小鼠，细胞凋亡显着增加迷走神经嵴细胞外的肠道。因此，Sox10和Sox8突变小鼠肠神经系统发育的缺陷可能是由未分化迷走神经嵴细胞库的减少引起的。我们的研究表明，Sox8和Sox10共同需要维持这些迷走神经嵴干细胞。(C)2004年爱思唯尔公司All rights reserved.
Mice carrying heterozygous mutations in the Sox10 gene display aganglionosis of the colon and represent a model for human Hirschsprung disease. Here, we show that the closely related Sox8 functions as a modifier gene for Sox10-dependent enteric nervous system defects as it increases both penetrance and severity of the defect in Sox10 heterozygous mice despite having no detectable influence on enteric nervous system development on its own. Sox8 exhibits an expression pattern very similar to Sox10 with occurrence in vagal and enteric neural crest cells and later confinement to enteric glia. Loss of Sox8 alleles in Sox10 heterozygous mice impaired colonization of the gut by enteric neural crest cells already at early times. Whereas proliferation, apoptosis, and neuronal differentiation were normal for enteric neural crest cells in the gut of mutant mice, apoptosis was dramatically increased in vagal neural crest cells outside the gut. The defects in enteric nervous system development of mice with Sox10 and Sox8 mutations are therefore likely caused by a reduction of the pool of undifferentiated vagal neural crest cells. Our study suggests that Sox8 and Sox10 are jointly required for the maintenance of these vagal neural crest stem cells. (C) 2004 Elsevier Inc. All rights reserved.