Cdo Functions at Multiple Points in the Sonic Hedgehog Pathway, and Cdo-Deficient Mice Accurately Model Human Holoprosencephaly

Wei Zhang, Jong Sun Kang, Francesca Cole, Min Jeong Yi, Robert S. Krauss

Research output: Contribution to journalArticle

184 Scopus citations

Abstract

Holoprosencephaly (HPE), a common defect of human forebrain development, is associated with haploinsufficiency for genes encoding Sonic Hedgehog (SHH) pathway components. Clinical expression of HPE is extremely variable, but it is rarely associated with defects in other SHH-dependent structures, such as limbs. Here we report that mice lacking the transmembrane protein Cdo, previously implicated in myogenesis, display HPE with strain-specific severity and without limb defects, modeling human HPE and implicating modifier genes as a cause of variability. Shh target gene expression is reduced in the developing forebrains of Cdo-/- mice, and Cdo positively regulates Shh signaling in vitro. Our data suggest that Cdo enhances pathway activity in multiple ways, including at signal reception and via a parallel mechanism required at the level of Gli transcription factors. Specific Cdo domains required for its promyogenic effect are dispensable for its Shh signaling role, suggesting that Cdo has multiple, independent functions.

Original languageEnglish (US)
Pages (from-to)657-665
Number of pages9
JournalDevelopmental cell
Volume10
Issue number5
DOIs
StatePublished - May 1 2006

Keywords

  • DEVBIO
  • SIGNALING

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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