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| Item Type: | Article |
|---|---|
| Title: | GAS1 is required for Notch-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium |
| Creators Name: | Marczenke, M., Sunaga, D., Popp, O., Althaus, I.W., Sauer, S., Mertins, P., Christ, A., Allen, B.L. and Willnow, T.E. |
| Abstract: | Growth arrest-specific 1 (GAS1) acts as a co-receptor to Patched 1 promoting sonic hedgehog (SHH) signaling in the developing nervous system. GAS1 mutations in humans and animal models result in forebrain and craniofacial malformations, defects ascribed to a function for GAS1 in SHH signaling during early neurulation. Here, we confirm loss of SHH activity in the forebrain neuroepithelium in GAS1-deficient mice and in iPSC-derived cell models of human neuroepithelial differentiation. However, our studies document that this defect can be attributed, at least in part, to a novel role for GAS1 in facilitating Notch signaling, essential to sustain a persistent SHH activity domain in the forebrain neuroepithelium. GAS1 directly binds NOTCH1, enhancing ligand-induced processing of the NOTCH1 intracellular domain, which drives Notch pathway activity in the developing forebrain. Our findings identify a unique role for GAS1 in integrating Notch and SHH signal reception in neuroepithelial cells, and they suggest that loss of GAS1-dependent NOTCH1 activation contributes to forebrain malformations in individuals carrying GAS1 mutations. |
| Keywords: | Forebrain Organizer Region, Holoprosencephaly, NOTCH Intracellular Domain, Neuroepithelial Precursor Cells, HH Co-Receptors, Animals, Mice |
| Source: | Development |
| ISSN: | 0950-1991 |
| Publisher: | Company of Biologists |
| Volume: | 148 |
| Number: | 21 |
| Page Range: | dev200080 |
| Date: | 11 November 2021 |
| Official Publication: | https://doi.org/10.1242/dev.200080 |
| PubMed: | View item in PubMed |
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