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

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

doi:10.1242/dev.200080

Abstract

ABSTRACTGrowth 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.

Highlights

The mammalian forebrain develops from a simple neuroepithelial sheet at the anterior end of the neural plate, the anterior neuroectoderm
Growth arrest-specific 1 (GAS1) mutations in humans and animal models result in forebrain and craniofacial malformations, defects ascribed to a function for GAS1 in sonic hedgehog (SHH) signaling during early neurulation
Our studies document that this defect can be attributed, at least in part, to a novel role for GAS1 in facilitating Notch signaling, essential to sustain a persistent SHH activity domain in the forebrain neuroepithelium

Summary

Introduction

The mammalian forebrain develops from a simple neuroepithelial sheet at the anterior end of the neural plate, the anterior neuroectoderm. In the embryonic forebrain, SHH is initially produced from the prechordal plate (PrCP) at the anterior tip of the embryo. It acts on the overlying rostral diencephalon ventral midline (RDVM) to induce its own production and the expression of ventral forebrain markers. Inheritable mutations in components of the SHH signaling pathway have been associated with human HPE, including mutations in SHH, in its receptor Patched 1 (PTCH1), or in downstream transcription factors, like GLI family zinc finger 2 (GLI2), SIX homeobox 3 (SIX3), and zinc finger protein of the cerebellum 2 (ZIC2) (Roessler and Muenke, 2010)

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