L1cam acts as a modifier gene for members of the endothelin signalling pathway during enteric nervous system development
L1cam acts as a modifier gene for members of the endothelin signalling pathway during enteric nervous system development
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DOI：
10.1111/j.1365-2982.2011.01692.x
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发表时间：
2011-11-01
影响因子：
3.5
通讯作者：
Anderson, R. B.
中科院分区：
文献类型：
--
作者：
Wallace, A. S.;Tan, M. X.;Anderson, R. B.
背景肠神经系统起源于神经嵴细胞，神经嵴细胞迁移到胚胎前肠，然后依次移殖到中肠和后肠。神经嵴迁移的缺陷导致肠道区域缺乏肠神经节，这是一种称为先天性巨结肠的人类疾病。在先天性巨结肠症中报告的高度表型变异表明修饰基因的参与。方法我们采用双位点互补的方法来筛选L1 cam和内皮素信号通路成员之间的遗传相互作用。用免疫组织化学方法标记大鼠胚胎小肠PGP9.5（+）肠神经元和Sox 10（+）神经嵴源性细胞。关键结果L1 cam的缺失或单倍不足显著增加了Et-3和Ednrb无效突变胚胎中无神经节细胞症的严重程度。此外，在L1 cam（-/y）; Et-3（-/-）和L1 cam（-/y）; Ednrb（sl/sl）胚胎中，神经嵴来源的细胞在发育中的肠道中的定殖显著延迟。结论与推论我们已经确定了X连锁基因，L1 CAM，作为第一个修饰基因的成员内皮素信号通路在肠神经系统的发展。在某些先天性巨结肠病例中，L1 CAM的突变可能调节无神经节细胞症的严重程度。
Background The enteric nervous system originates from neural crest cells that migrate into the embryonic foregut and then sequentially colonize the midgut and hindgut. Defects in neural crest migration result in regions of the gut that lack enteric ganglia, a condition in humans called Hirschsprung's disease. The high degree of phenotypic variability reported in Hirschsprung's disease suggests the involvement of modifier genes. Methods We used a two-locus complementation approach to screen for genetic interactions between L1cam and members of the endothelin signalling pathway. Immunohistochemistry was used to label PGP9.5(+) enteric neurons and Sox10(+) neural crest-derived cells in wholemount preparations of embryonic gut. Key Results Loss or haploinsufficiency of L1cam significantly increased the severity of aganglionosis in Et-3 and Ednrb null mutant embryos. Furthermore, the colonization of the developing gut by neural crest-derived cells was significantly delayed in L1cam(-/y); Et-3(-/-) and L1cam(-/y); Ednrb(sl/sl) embryos. Conclusions & Inferences We have identified the X-linked gene, L1cam, as the first modifier gene for members of the endothelin signalling pathway during development of the enteric nervous system. Mutations in L1CAM may act to modulate the severity of aganglionosis in some cases of Hirschsprung's disease.