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Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development

Chris Cho1, Yanshu Wang1,2, Philip M Smallwood1,2

  • 1Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, United States.

Elife
|June 22, 2019
PubMed

Insights

Reck protein specifically enhances Wnt7a/Wnt7b signaling, crucial for central nervous system (CNS) angiogenesis. Mutations in Reck disrupt this signaling, leading to severe developmental defects in mouse embryos.

Area of Science:

  • Developmental Biology
  • Molecular Biology
  • Neuroscience

Background:

  • Wnt-Frizzled signaling pathways regulate crucial developmental processes.
  • Specificity of Wnt ligands binding to Frizzled receptors remains incompletely understood.
  • Reck and Gpr124 are implicated in modulating specific Wnt signaling events.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying Wnt7a and Wnt7b specificity mediated by Reck and Gpr124.
  • To identify key regions within Wnt7a/Wnt7b and Reck essential for this specific signaling.
  • To investigate the in vivo role of Reck in central nervous system (CNS) development.

Main Methods:

  • Site-directed mutagenesis to identify critical amino acid residues in Wnt7a/Wnt7b.
  • Analysis of Reck protein domains, specifically the CC domain, using targeted substitutions.
  • Assessment of Reck function in mouse embryos to study its role in CNS angiogenesis.

Main Results:

  • Two distinct amino acid clusters in Wnt7a/Wnt7b are essential for Reck- and Gpr124-dependent signaling.
  • Specific mutations within the CC4 domain of Reck abolish Wnt7a stimulation without affecting protein stability or localization.
  • Mouse embryos with Reck mutations exhibit severe forebrain angiogenesis defects.

Conclusions:

  • Reck acts as a specificity factor, enhancing beta-catenin signaling by Wnt7a and Wnt7b through interaction with Gpr124.
  • Critical Wnt7a/Wnt7b residues and Reck CC4 domain are vital for this specialized signaling.
  • Reck plays a critical role in promoting CNS angiogenesis by specifically activating Wnt7a/Wnt7b pathways.
Keywords:
CNS angiogenesisGpr124ReckWnt7blood-brain barriercanonical Wnt signalingdevelopmental biologymouseneuroscience

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