GDE2 Promotes Neurogenesis by Glycosylphosphatidylinositol-Anchor Cleavage of RECK

Abstract

The six-transmembrane protein glycerophosphodiester phosphodiesterase 2 (GDE2) induces spinal motor neuron differentiation by inhibiting Notch signaling in adjacent motor neuron progenitors. GDE2 function requires activity of its extracellular domain that shares homology with glycerophosphodiester phosphodiesterases (GDPD). GDPDs metabolize glycerophosphodiesters into glycerol-3-phosphate and corresponding alcohols but whether GDE2 inhibits Notch signaling by this mechanism is unclear. Here, we show that GDE2, unlike classical GDPDs, cleaves glycosylphosphatidylinositol (GPI)-anchors. GDE2 GDPD activity inactivates the Notch activator RECK by releasing it from the membrane by GPI-anchor cleavage. RECK release disinhibits ADAM protease-dependent shedding of the Notch ligand Delta-like 1 (Dll1) leading to Notch inactivation. This study identifies a previously unrecognized mechanism to initiate neurogenesis that involves GDE2 mediated surface cleavage of GPI-anchored targets to inhibit Dll1-Notch signaling.

Reck enables cerebrovascular development by promoting canonical Wnt signaling

“…Finally, consistent with its multi-domain structure, Reck associates with the ERBB2 receptor to block its activity in an MP-independent fashion (Hong et al, 2011). Reck modulates the development of forelimbs, dorsal root ganglia neurons (DRG), brain (Muraguchi et al, 2007;Park et al, 2013;Prendergast et al, 2012;Yamamoto et al, 2012) and vasculature. Reck-knockout mice show perineural vascular plexus disorganization and reduced intracerebral vascularization (Chandana et al, 2010;Miki et al, 2010;Oh et al, 2001).…”

Thematic Review Series: Glycosylphosphatidylinositol (GPI) Anchors: Biochemistry and Cell Biology Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling

“…Because of GPI modifi cation, mammalian GPI-APs have unique characteristics, such as association with membrane microdomains or membrane rafts enriched in sphingolipids and cholesterol ( 10 ), transient homodimerization ( 11 ), release from the membrane by cleavage in the GPI moiety (12)(13)(14)(15), and apical sorting in polarized cells ( 16 ). GPI anchoring of proteins is essential for mammalian embryogenesis, development, neurogenesis, fertilization, and immune system ( 12,14,(17)(18)(19)(20)(21). Yeast Saccharomyces cerevisiae has >60 GPI-APs.…”

Mutations in the phosphatidylinositol glycan C (PIGC) gene are associated with epilepsy and intellectual disability

“…In mammals there are over 150 GPI-APs, including receptors, adhesion molecules and enzymes; many of them are critical for normal neural and embryonic development 9 10. GPI is a glycolipid structure that is synthesised and remodelled in a multistep process requiring around 30 proteins; it is formed in the endoplasmic reticulum, where it is attached by the GPI transamidase to a protein showing a specific C-terminal signal before it is transported to the Golgi apparatus for fatty acid remodelling and cellular exporting 11.…”