A conserved Pbx-Wnt-p63-Irf6 regulatory module controls face morphogenesis by promoting epithelial apoptosis.


Journal Article

Morphogenesis of mammalian facial processes requires coordination of cellular proliferation, migration, and apoptosis to develop intricate features. Cleft lip and/or palate (CL/P), the most frequent human craniofacial birth defect, can be caused by perturbation of any of these programs. Mutations of WNT, P63, and IRF6 yield CL/P in humans and mice; however, how these genes are regulated remains elusive. We generated mouse lines lacking Pbx genes in cephalic ectoderm and demonstrated that they exhibit fully penetrant CL/P and perturbed Wnt signaling. We also characterized a midfacial regulatory element that Pbx proteins bind to control the expression of Wnt9b-Wnt3, which in turn regulates p63. Altogether, we establish a Pbx-dependent Wnt-p63-Irf6 regulatory module in midfacial ectoderm that is conserved within mammals. Dysregulation of this network leads to localized suppression of midfacial apoptosis and CL/P. Ectopic Wnt ectodermal expression in Pbx mutants rescues the clefting, opening avenues for tissue repair.

Full Text

Duke Authors

Cited Authors

  • Ferretti, E; Li, B; Zewdu, R; Wells, V; Hebert, JM; Karner, C; Anderson, MJ; Williams, T; Dixon, J; Dixon, MJ; Depew, MJ; Selleri, L

Published Date

  • October 18, 2011

Published In

Volume / Issue

  • 21 / 4

Start / End Page

  • 627 - 641

PubMed ID

  • 21982646

Pubmed Central ID

  • 21982646

Electronic International Standard Serial Number (EISSN)

  • 1878-1551

Digital Object Identifier (DOI)

  • 10.1016/j.devcel.2011.08.005


  • eng

Conference Location

  • United States