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

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DOI

  • Maike Marczenke, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Free University of Berlin
  • ,
  • Daniele Yumi Sunaga-Franze, Max Delbrück Center for Molecular Medicine in the Helmholtz Association
  • ,
  • Oliver Popp, Max Delbrück Center for Molecular Medicine in the Helmholtz Association
  • ,
  • Irene W. Althaus, University of Michigan, Ann Arbor
  • ,
  • Sascha Sauer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association
  • ,
  • Philipp Mertins, Max Delbrück Center for Molecular Medicine in the Helmholtz Association
  • ,
  • Annabel Christ, Max Delbrück Center for Molecular Medicine in the Helmholtz Association
  • ,
  • Benjamin L. Allen, University of Michigan, Ann Arbor
  • ,
  • Thomas E. Willnow

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.

Original languageEnglish
JournalDevelopment (Cambridge)
Volume148
Issue21
ISSN0950-1991
DOIs
Publication statusPublished - Nov 2021

Bibliographical note

Publisher Copyright:
© 2021. Published by The Company of Biologists Ltd

    Research areas

  • Forebrain organizer region, HH co-receptors, Holoprosencephaly, Neuroepithelial precursor cells, NOTCH intracellular domain

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