Reck and Gpr124 Are Essential Receptor Cofactors for Wnt7a/Wnt7b-Specific Signaling in Mammalian CNS Angiogenesis and Blood-Brain Barrier Regulation

Abstract

Summary Reck, a GPI-anchored membrane protein, and Gpr124, an orphan GPCR, have been implicated in Wnt7a/Wnt7b signaling in the CNS vasculature. We show here that vascular endothelial cell (EC)-specific reduction in Reck impairs CNS angiogenesis and that EC-specific postnatal loss of Reck combined with loss of Norrin impairs blood-brain barrier (BBB) maintenance. The most N-terminal domain of Reck binds to the leucine-rich repeat (LRR) and immunoglobulin (Ig) domains of Gpr124, and weakening this interaction by targeted mutagenesis reduces Reck/Gpr124 stimulation of Wnt7a signaling in cell culture and impairs CNS angiogenesis. Finally, a soluble Gpr124(LRR-Ig) probe binds to cells expressing Frizzled, Wnt7a or Wnt7b, and Reck; and a soluble Reck(CC1–5) probe binds to cells expressing Frizzled, Wnt7a or Wnt7b, and Gpr124. These experiments indicate that Reck and Gpr124 are part of the cell-surface protein complex that transduces Wnt7a- and Wnt7b-specific signals in mammalian CNS ECs to promote angiogenesis and regulate the BBB.

Effects of treadmill exercise on cerebral angiogenesis and MT1‐MMP expression after cerebral ischemia in rats

“…Reversion‐inducing cysteine‐rich protein with Kazalmotifs genes are divided into two kinds in vivo, that is, membrane RECK and soluble RECK (Cho, Smallwood, & Nathans, 2017); bothcan be weakly expressed in normal tissues. Studies have shown that post‐transcriptional RECK can inhibit MT1‐MMP.…”

Endothelial GPR124 Exaggerates the Pathogenesis of Atherosclerosis by Activating Inflammation

“…GPR124 exhibits neuronal and non-neuronal expression profiles [8, 9]. GPR124 expression during capillary morphogenesis is induced by the small GTPase Rac and mediates the contact inhibition of proliferation in endothelial cells during angiogenesis [10].…”

“…GPR124 functions cell autonomously in the endothelium to regulate sprouting migration, and the developmental expression of the Glucose transporter 1 (Glut1) [8]. Gpr124 was identified as a ligand-specific coactivator of canonical Wnt signaling [13].…”

Retinoic acid signaling in vascular development

“…Wntdriven vascularization of the CNS is largely mediated by canonical Wnt signaling via the Lrp5/6 receptors and β-catenin transcriptional activity . Transduction of Wnt7a/7b binding to the Frizzled/LRP receptors is achieved through the G-coupled protein receptor, Gpr124 and its co-factor, Reck (C. Cho, Smallwood, & Nathans, 2017;.…”