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

Chris Cho, Philip M. Smallwood, Jeremy Nathans

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1056-1073.e5
JournalNeuron
Volume95
Issue number5
DOIs
StatePublished - Aug 30 2017

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Blood-Brain Barrier
Leucine
Membrane Proteins
Endothelial Cells
Mutagenesis
Immunoglobulins
Cell Culture Techniques
Maintenance
Immunoglobulin Domains

Keywords

  • blood-brain barrier
  • canonical Wnt signaling
  • CNS angiogenesis
  • mouse genetics
  • vascular endothelial cells
  • Wnt reporter

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Reck and Gpr124 Are Essential Receptor Cofactors for Wnt7a/Wnt7b-Specific Signaling in Mammalian CNS Angiogenesis and Blood-Brain Barrier Regulation. / Cho, Chris; Smallwood, Philip M.; Nathans, Jeremy.

In: Neuron, Vol. 95, No. 5, 30.08.2017, p. 1056-1073.e5.

Research output: Contribution to journalArticle

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