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Marczenke M, Sunaga-Franze DY, Popp O, et al. GAS1 is required for NOTCH-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium. Development. 2021;148(21)doi: 10.1242/dev.200080.
Marczenke, M., Sunaga-Franze, D. Y., Popp, O., Althaus, I. W., Sauer, S., Mertins, P., Christ, A., Allen, B. L., & Willnow, T. E. (2021). GAS1 is required for NOTCH-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium. Development (Cambridge, England), 148(21), . https://doi.org/10.1242/dev.200080
Marczenke, Maike, et al. "GAS1 is required for NOTCH-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium." Development (Cambridge, England) vol. 148,21 (2021). doi: https://doi.org/10.1242/dev.200080
Marczenke M, Sunaga-Franze DY, Popp O, Althaus IW, Sauer S, Mertins P, Christ A, Allen BL, Willnow TE. GAS1 is required for NOTCH-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium. Development. 2021 Nov 01;148(21). doi: 10.1242/dev.200080. Epub 2021 Nov 11. PMID: 34698766; PMCID: PMC8627604.
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Development. 2021 Nov 01;148(21). doi: 10.1242/dev.200080. Epub 2021 Nov 11.

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

Development (Cambridge, England)

Maike Marczenke, Daniele Yumi Sunaga-Franze, Oliver Popp, Irene W Althaus, Sascha Sauer, Philipp Mertins, Annabel Christ, Benjamin L Allen, Thomas E Willnow

Affiliations

  1. Molecular Physiology, Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany.
  2. Department of Biology, Chemistry and Pharmacy, Freie Universitaet Berlin, 12169 Berlin, Germany.
  3. Genomics Platform, Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany.
  4. Proteomics Platform, Max-Delbrueck-Center for Molecular Medicine, 13125 Berlin, Germany.
  5. Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  6. Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.

PMID: 34698766 PMCID: PMC8627604 DOI: 10.1242/dev.200080

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 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.

© 2021. Published by The Company of Biologists Ltd.

Keywords: Forebrain organizer region; HH co-receptors; Holoprosencephaly; NOTCH intracellular domain; Neuroepithelial precursor cells

Conflict of interest statement

Competing interests The authors declare no competing or financial interests.

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