Abstract
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.
Highlights
The development of the vertebrate brain is complex and requires a tightly controlled spatial and temporal orchestration of numerous signalling pathways
Using chick and mouse embryonic models, we demonstrate that embryos lacking ted NOTCH activity during early forebrain development exhibit a specific reduction of Sonic Hedgehog (SHH) signalling in the anterior hypothalamus
Sonic hedgehog signalling was active in the presumptive hypothalamus before NOTCH activity in the chick embryo t To analyse the potential interaction between NOTCH and SHH signalling at the level of the ip developing hypothalamus, the chick was used as a model since molecular features defining the anteror posterior domains have been extensively described (10, 37)
Summary
The development of the vertebrate brain is complex and requires a tightly controlled spatial and temporal orchestration of numerous signalling pathways. Among these pathways is Sonic Hedgehog (SHH), an essential morphogenetic signal dictating cell fate decisions during early forebrain development (1). Both embryological evidence in chick and genetic evidence in mouse have shown t that SHH secreted by the axial mesoderm underlying the neural plate initiates development of the ip ventral midline (2, 3). During hypothalamic sc patterning, SHH acts as a local signal to subdivide the developing hypothalamus into subregions u (4, 5). The anterior hypothalamus is the a first region to produce differentiated neurons giving rise to the tract of the postoptic commissure (6)
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