Univ Rennes, CNRS, IGDR - Institut de Génétique et Développement de Rennes - UMR6290, Rennes, France.
Service de Génétique Moléculaire et Génomique, CHU, Rennes, France.
J Clin Endocrinol Metab. 2020 Sep 1;105(9). doi: 10.1210/clinem/dgaa249.
In human, Sonic hedgehog (SHH) haploinsufficiency is the predominant cause of holoprosencephaly, a structural malformation of the forebrain midline characterized by phenotypic heterogeneity and incomplete penetrance. The NOTCH signaling pathway has recently been associated with holoprosencephaly in humans, but the precise mechanism involving NOTCH signaling during early brain development remains unknown.
The aim of this study was to evaluate the relationship between SHH and NOTCH signaling to determine the mechanism by which NOTCH dysfunction could cause midline malformations of the forebrain.
In this study, we have used a chemical inhibition approach in the chick model and a genetic approach in the mouse model. We also reported results obtained from the clinical diagnosis of a cohort composed of 141 holoprosencephaly patients.
We demonstrated that inhibition of NOTCH signaling in chick embryos as well as in mouse embryos induced a specific downregulation of SHH in the anterior hypothalamus. Our data in the mouse also revealed that the pituitary gland was the most sensitive tissue to Shh insufficiency and that haploinsufficiency of the SHH and NOTCH signaling pathways synergized to produce a malformed pituitary gland. Analysis of a large holoprosencephaly cohort revealed that some patients possessed multiple heterozygous mutations in several regulators of both pathways.
These results provided new insights into molecular mechanisms underlying the extreme phenotypic variability observed in human holoprosencephaly. They showed how haploinsufficiency of the SHH and NOTCH activity could contribute to specific congenital hypopituitarism that was associated with a sella turcica defect.
在人类中，Sonic 刺猬hog（SHH）单倍不足是全前脑无脑畸形的主要原因，这是一种前脑中线结构畸形，表现型异质性和不完全外显率。最近，NOTCH 信号通路与人类全前脑无脑畸形有关，但在早期大脑发育过程中涉及 NOTCH 信号的精确机制尚不清楚。
本研究旨在评估 SHH 和 NOTCH 信号之间的关系，以确定 NOTCH 功能障碍如何导致前脑中线畸形的机制。
在这项研究中，我们使用了化学抑制方法在鸡模型中，以及在小鼠模型中使用了遗传方法。我们还报告了由 141 例全前脑无脑畸形患者组成的队列的临床诊断结果。
我们证明了在鸡胚和小鼠胚胎中抑制 NOTCH 信号会导致前下丘脑 SHH 的特异性下调。我们在小鼠中的数据还表明，垂体是对 Shh 不足最敏感的组织，并且 SHH 和 NOTCH 信号通路的单倍不足协同作用产生了畸形的垂体。对大的全前脑无脑畸形队列的分析表明，一些患者在两个通路的几个调节因子中都存在多个杂合突变。
这些结果为人类全前脑无脑畸形中观察到的极端表型变异性的分子机制提供了新的见解。它们显示了 SHH 和 NOTCH 活性的单倍不足如何导致与鞍区缺陷相关的特定先天性垂体功能减退。
