A Conserved Pbx-Wnt-p63-Irf6 Regulatory Module Controls Face Morphogenesis by Promoting Epithelial Apoptosis

Elisabetta Ferretti, Bingsi Li, Rediet Zewdu, Victoria Wells, Jean M. Hebert, Courtney Karner, Matthew J. Anderson, Trevor Williams, Jill Dixon, Michael J. Dixon, Michael J. Depew, Licia Selleri

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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. © 2011 Elsevier Inc.
    Original languageEnglish
    Pages (from-to)627-641
    Number of pages14
    JournalDevelopmental cell
    Volume21
    Issue number4
    DOIs
    Publication statusPublished - 18 Oct 2011

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