A vertebrate Vangl2 translational variant required for planar cell polarity

J Biol Chem. 2024 Apr;300(4):106792. doi: 10.1016/j.jbc.2024.106792. Epub 2024 Feb 24.

Abstract

First described in the milkweed bug Oncopeltus fasciatus, planar cell polarity (PCP) is a developmental process essential for embryogenesis and development of polarized structures in Metazoans. This signaling pathway involves a set of evolutionarily conserved genes encoding transmembrane (Vangl, Frizzled, Celsr) and cytoplasmic (Prickle, Dishevelled) molecules. Vangl2 is of major importance in embryonic development as illustrated by its pivotal role during neural tube closure in human, mouse, Xenopus, and zebrafish embryos. Here, we report on the molecular and functional characterization of a Vangl2 isoform, Vangl2-Long, containing an N-terminal extension of about 50 aa, which arises from an alternative near-cognate AUA translation initiation site, lying upstream of the conventional start codon. While missing in Vangl1 paralogs and in all invertebrates, including Drosophila, this N-terminal extension is conserved in all vertebrate Vangl2 sequences. We show that Vangl2-Long belongs to a multimeric complex with Vangl1 and Vangl2. Using morpholino oligonucleotides to specifically knockdown Vangl2-Long in Xenopus, we found that this isoform is functional and required for embryo extension and neural tube closure. Furthermore, both Vangl2 and Vangl2-Long must be correctly expressed for the polarized distribution of the PCP molecules Pk2 and Dvl1 and for centriole rotational polarity in ciliated epidermal cells. Altogether, our study suggests that Vangl2-Long significantly contributes to the pool of Vangl2 molecules present at the plasma membrane to maintain PCP in vertebrate tissues.

Keywords: PCP; Xenopus; isoform; translation; vangl2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins
  • Cell Polarity*
  • Dishevelled Proteins* / genetics
  • Dishevelled Proteins* / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins* / genetics
  • Intracellular Signaling Peptides and Proteins* / metabolism
  • Membrane Proteins* / genetics
  • Membrane Proteins* / metabolism
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Protein Biosynthesis
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Xenopus Proteins / genetics
  • Xenopus Proteins / metabolism
  • Xenopus laevis
  • Zebrafish / genetics
  • Zebrafish / metabolism
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism

Substances

  • Carrier Proteins
  • Dishevelled Proteins
  • DVL1 protein, human
  • DVL1 protein, Xenopus
  • Intracellular Signaling Peptides and Proteins
  • Ltap protein, mouse
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Protein Isoforms
  • VANGL1 protein, human
  • Vangl1 protein, mouse
  • VANGL2 protein, human
  • Vangl2 protein, Xenopus
  • vangl2 protein, zebrafish
  • Xenopus Proteins
  • Zebrafish Proteins