Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, United States.
Max-Delbruck-Center for Molecular Medicine, Berlin, Germany.
Elife. 2020 Sep 2;9:e60351. doi: 10.7554/eLife.60351.
Holoprosencephaly (HPE), a defect in midline patterning of the forebrain and midface, arises ~1 in 250 conceptions. It is associated with predisposing mutations in the Nodal and Hedgehog (HH) pathways, with penetrance and expressivity graded by genetic and environmental modifiers, via poorly understood mechanisms. CDON is a multifunctional co-receptor, including for the HH pathway. In mice, mutation synergizes with fetal alcohol exposure, producing HPE phenotypes closely resembling those seen in humans. We report here that, unexpectedly, Nodal signaling is a major point of synergistic interaction between mutation and fetal alcohol. Window-of-sensitivity, genetic, and in vitro findings are consistent with a model whereby brief exposure of mutant embryos to ethanol during gastrulation transiently and partially inhibits Nodal pathway activity, with consequent effects on midline patterning. These results illuminate mechanisms of gene-environment interaction in a multifactorial model of a common birth defect.
前脑和中面部中线模式形成缺陷导致的无脑回畸形（HPE），在约每 250 例妊娠中出现 1 例。它与 Nodal 和 Hedgehog（HH）通路中的潜在突变有关，通过遗传和环境修饰物的作用，其外显率和表现度呈梯度分布，其机制尚不清楚。CDON 是一种多功能的共受体，包括 HH 通路。在小鼠中，突变与胎儿酒精暴露协同作用，产生的 HPE 表型与人类所见非常相似。我们在这里报告的是，出乎意料的是，Nodal 信号是突变和胎儿酒精之间协同相互作用的主要关键点。时间窗敏感性、遗传和体外研究结果一致表明，在原肠胚形成期间，短暂暴露于乙醇可使突变胚胎的 Nodal 通路活性暂时和部分受到抑制，从而对中线模式形成产生影响。这些结果阐明了在常见出生缺陷的多因素模型中基因-环境相互作用的机制。
