Disrupted Hypothalamo-Pituitary Axis in Association With Reduced SHH Underlies the Pathogenesis of NOTCH-Deficiency

Abstract

Context 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. Objective 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. Design 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. Results 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. Conclusions 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.

Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic

“…However, a large-scale study would be needed to confirm our findings. One possibility consistent with these observations is that congenital hypopituitarism often has a digenic or oligogenic inheritance, as has been suggested (Hamdi-Rozé et al, 2020), although data for this hypothesis has been reported only in a small number of families to date (Zwaveling-Soonawala et al, 2018). In our study, 2 out of 13 families showed a possible oligogenic etiology.…”

A neuroepithelial wave of BMP signalling drives anteroposterior specification of the tuberal hypothalamus

“…By contrast, HES5 expression is dramatically reduced in BMP-exposed embryos (Figure 6Q, S-S”, U’). Notch maintains the progenitor state in chicken hypothalamus (Hamdi-Rozé et al, 2020, Place et al, 2022, Ratié et al, 2013, Ratié et al, 2014, Ware et al, 2016) so the loss of HES5 in BMP-treated embryos may be associated with ectopic neurogenesis. Despite this result, no clear differences in DLL1 and ELAVL4 expression were seen in the residual hypothalamic domain in BMP-treated embryos (Figure 6Q, U’).…”

“…BMPs and low WNT levels direct the specification of posterior tuberal progenitors, through upregulation of TBX2/FGF10; TBX2/TBX3 in turn downregulate SHH (Manning et al, 2006; Trowe et al, 2013). SHH and Notch signalling, by contrast, direct anterior tuberal progenitor growth and neurogenesis (Blaess et al, 2014, Carreno et al, 2017, Corman et al, 2018, Dupé et al, 2011, Fu et al, 2017, Ratié et al, 2013, Shimogori et al, 2010, Aujla et al, 2013, Hamdi-Rozé et al, 2020, Orquera et al, 2016, Ratié et al, 2014, Szabó et al, 2009, Ware et al, 2016). Studies in mouse furthermore suggest that a delicate balance of SHH and BMP signalling directs tuberal hypothalamic development (Corman et al, 2018).…”

GAS1 is required for NOTCH-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium

“…Haploinsufficiency for NOTCH pathway components in some patients with HPE further suggests that NOTCH-dependent facilitation of SHH signaling is required for forebrain formation (Dupe et al, 2011). This conclusion is supported by loss of NOTCH-dependent SHH activity in the embryonic mouse and chick forebrains following pharmacological or genetic perturbation of NOTCH activity, defects that include disruption of the hypothalamopituitary axis (Hamdi-Roze et al, 2020).…”