| First Author | Marczenke M | Year | 2021 |
| Journal | Development | Volume | 148 |
| Issue | 21 | PubMed ID | 34698766 |
| Mgi Jnum | J:314133 | Mgi Id | MGI:6814648 |
| Doi | 10.1242/dev.200080 | Citation | Marczenke M, et al. (2021) GAS1 is required for NOTCH-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium. Development 148(21):dev200080 |
| abstractText | 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 induced pluripotent stem cell-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, which is 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. |
