Disrupted hypothalamo-pituitary axis in association with reduced SHH underlies the pathogenesis of NOTCH-deficiency.

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In human, Sonic Hedgehog, SHH, haploinsufficiency is the predominant cause of holoprosencephaly, a structural malformation of the forebrain midline characterised by phenotypic heterogeneity and incomplete penetrance. The NOTCH signalling pathway has recently been associated with holoprosencephaly, in humans, but the precise mechanism involving NOTCH signalling during early brain development remains unknown.The aim of this study was to evaluate the relationship between SHH and NOTCH signalling in order 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 reported results obtained from clinical diagnosis of a cohort composed of 141 holoprosencephaly patients.We demonstrated that inhibition of NOTCH signalling in chick embryos as well as in mouse embryos induces 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 signalling 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.

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