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 journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)627-641
Number of pages15
JournalDevelopmental Cell
Volume21
Issue number4
DOIs
StatePublished - Oct 18 2011

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Cleft Lip
Cleft Palate
Morphogenesis
Ectoderm
Genes
Apoptosis
Mammals
Repair
Tissue
Defects
Head
Cell Proliferation
Mutation
Proteins

ASJC Scopus subject areas

  • Developmental Biology

Cite this

A Conserved Pbx-Wnt-p63-Irf6 Regulatory Module Controls Face Morphogenesis by Promoting Epithelial Apoptosis. / Ferretti, Elisabetta; Li, Bingsi; Zewdu, Rediet; Wells, Victoria; Hebert, Jean M.; Karner, Courtney; Anderson, Matthew J.; Williams, Trevor; Dixon, Jill; Dixon, Michael J.; Depew, Michael J.; Selleri, Licia.

In: Developmental Cell, Vol. 21, No. 4, 18.10.2011, p. 627-641.

Research output: Contribution to journalArticle

Ferretti, E, Li, B, Zewdu, R, Wells, V, Hebert, JM, Karner, C, Anderson, MJ, Williams, T, Dixon, J, Dixon, MJ, Depew, MJ & Selleri, L 2011, 'A Conserved Pbx-Wnt-p63-Irf6 Regulatory Module Controls Face Morphogenesis by Promoting Epithelial Apoptosis', Developmental Cell, vol. 21, no. 4, pp. 627-641. https://doi.org/10.1016/j.devcel.2011.08.005
Ferretti, Elisabetta ; Li, Bingsi ; Zewdu, Rediet ; Wells, Victoria ; Hebert, Jean M. ; Karner, Courtney ; Anderson, Matthew J. ; Williams, Trevor ; Dixon, Jill ; Dixon, Michael J. ; Depew, Michael J. ; Selleri, Licia. / A Conserved Pbx-Wnt-p63-Irf6 Regulatory Module Controls Face Morphogenesis by Promoting Epithelial Apoptosis. In: Developmental Cell. 2011 ; Vol. 21, No. 4. pp. 627-641.
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