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GAS1 is required for NOTCH-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium. / Marczenke, Maike; Sunaga-Franze, Daniele Yumi; Popp, Oliver et al.
In: Development (Cambridge), Vol. 148, No. 21, 11.2021.Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review
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TY - JOUR
T1 - GAS1 is required for NOTCH-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium
AU - Marczenke, Maike
AU - Sunaga-Franze, Daniele Yumi
AU - Popp, Oliver
AU - Althaus, Irene W.
AU - Sauer, Sascha
AU - Mertins, Philipp
AU - Christ, Annabel
AU - Allen, Benjamin L.
AU - Willnow, Thomas E.
N1 - Publisher Copyright: © 2021. Published by The Company of Biologists Ltd
PY - 2021/11
Y1 - 2021/11
N2 - 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.
AB - 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.
KW - Forebrain organizer region
KW - HH co-receptors
KW - Holoprosencephaly
KW - Neuroepithelial precursor cells
KW - NOTCH intracellular domain
UR - http://www.scopus.com/inward/record.url?scp=85120789106&partnerID=8YFLogxK
U2 - 10.1242/dev.200080
DO - 10.1242/dev.200080
M3 - Journal article
C2 - 34698766
AN - SCOPUS:85120789106
VL - 148
JO - Development (Cambridge, England)
JF - Development (Cambridge, England)
SN - 0950-1991
IS - 21
ER -