Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/β-catenin signaling

Genes Dev. 2018 Nov 1;32(21-22):1443-1458. doi: 10.1101/gad.315531.118. Epub 2018 Oct 26.

Abstract

Bcl9 and Pygopus (Pygo) are obligate Wnt/β-catenin cofactors in Drosophila, yet their contribution to Wnt signaling during vertebrate development remains unresolved. Combining zebrafish and mouse genetics, we document a conserved, β-catenin-associated function for BCL9 and Pygo proteins during vertebrate heart development. Disrupting the β-catenin-BCL9-Pygo complex results in a broadly maintained canonical Wnt response yet perturbs heart development and proper expression of key cardiac regulators. Our work highlights BCL9 and Pygo as selective β-catenin cofactors in a subset of canonical Wnt responses during vertebrate development. Moreover, our results implicate alterations in BCL9 and BCL9L in human congenital heart defects.

Keywords: Wnt signaling; CRISPR–Cas9; cardiovascular development; congenital heart disease; heart; transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Heart / embryology
  • Heart Defects, Congenital / genetics*
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Mice
  • Mutation
  • Myocardium / metabolism
  • Transcription Factors / genetics*
  • Wnt Signaling Pathway*
  • Zebrafish / embryology
  • Zebrafish / genetics
  • Zebrafish Proteins / genetics*
  • beta Catenin / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • BCL9 protein, mouse
  • BCL9L protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Pygo1 protein, mouse
  • Transcription Factors
  • Zebrafish Proteins
  • beta Catenin
  • pygopus 2 protein, mouse