GAS1 is required for NOTCH-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium
© 2021. Published by The Company of Biologists Ltd..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:148 |
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| Enthalten in: |
Development (Cambridge, England) - 148(2021), 21 vom: 01. Nov. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Marczenke, Maike [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.12.2021 Date Revised 16.12.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1242/dev.200080 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021. Published by The Company of Biologists Ltd. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Forebrain organizer region | |
| 650 | 4 | |a HH co-receptors | |
| 650 | 4 | |a Holoprosencephaly | |
| 650 | 4 | |a NOTCH intracellular domain | |
| 650 | 4 | |a Neuroepithelial precursor cells | |
| 650 | 7 | |a Cell Cycle Proteins |2 NLM | |
| 650 | 7 | |a GPI-Linked Proteins |2 NLM | |
| 650 | 7 | |a Gas1 protein, mouse |2 NLM | |
| 650 | 7 | |a Hedgehog Proteins |2 NLM | |
| 650 | 7 | |a Notch1 protein, mouse |2 NLM | |
| 650 | 7 | |a Patched-1 Receptor |2 NLM | |
| 650 | 7 | |a Ptch1 protein, mouse |2 NLM | |
| 650 | 7 | |a Receptor, Notch1 |2 NLM | |
| 650 | 7 | |a Shh protein, mouse |2 NLM | |
| 700 | 1 | |a Sunaga-Franze, Daniele Yumi |e verfasserin |4 aut | |
| 700 | 1 | |a Popp, Oliver |e verfasserin |4 aut | |
| 700 | 1 | |a Althaus, Irene W |e verfasserin |4 aut | |
| 700 | 1 | |a Sauer, Sascha |e verfasserin |4 aut | |
| 700 | 1 | |a Mertins, Philipp |e verfasserin |4 aut | |
| 700 | 1 | |a Christ, Annabel |e verfasserin |4 aut | |
| 700 | 1 | |a Allen, Benjamin L |e verfasserin |4 aut | |
| 700 | 1 | |a Willnow, Thomas E |e verfasserin |4 aut | |
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