Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31225798.
- Also identified by DOI 10.7554/eLife.47300 and PMC identifier 6588345.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The molecular basis of Wnt-Frizzled specificity is a central question in developmental biology. Reck, a multi-domain and multi-functional glycosylphosphatidylinositol-anchored protein, specifically enhances beta-catenin signaling by Wnt7a and Wnt7b in cooperation with the 7-transmembrane protein Gpr124. Among amino acids that distinguish Wnt7a and Wnt7b from other Wnts, two clusters are essential for signaling in a Reck- and Gpr124-dependent manner. Both clusters are far from the site of Frizzled binding: one resides at the amino terminus and the second resides in a protruding loop. Within Reck, the fourth of five tandem repeats of an unusual domain with six-cysteines (the CC domain) is essential for Wnt7a stimulation: substitutions P256A and W261A in CC4 eliminate this activity without changing protein abundance or surface localization. Mouse embryos carrying <i>Reck<sup>P256A,W261A</sup></i> have severe defects in forebrain angiogenesis, providing the strongest evidence to date that Reck promotes CNS angiogenesis by specifically stimulating Wnt7a and Wnt7b signaling.
Medical subject headings
- Brain
- Frizzled Receptors
- GPI-Linked Proteins
- Signal Transduction
- Wnt Proteins