TY - JOUR
T1 - A Conserved Pbx-Wnt-p63-Irf6 Regulatory Module Controls Face Morphogenesis by Promoting Epithelial Apoptosis
AU - Ferretti, Elisabetta
AU - Li, Bingsi
AU - Zewdu, Rediet
AU - Wells, Victoria
AU - Hebert, Jean M.
AU - Karner, Courtney
AU - Anderson, Matthew J.
AU - Williams, Trevor
AU - Dixon, Jill
AU - Dixon, Michael J.
AU - Depew, Michael J.
AU - Selleri, Licia
N1 - Funding Information:
We are grateful to Drs. M. Lewandoski and T. Carroll for generously providing Fgf8 hypomorph embryos, Wnt9b- deficient mice, and Rosa-Wnt1 mice. We also thank Dr. D. Kingsley for the SfiHsp68LacZ plasmid; Dr. B. Wang for proliferation assays; Drs. E. Lacy, A. Foley, T. Capellini, and D. Noden for important discussions; and Cyagen for transgenic embryos. Work was supported by Marie Curie Fellowship (OIF-CT-2005-022003) to E.F., grants from MRC UK (G0901539) to J.D. and M.J. Dixon, the Royal Society and King's College London to M.J. Depew, and March of Dimes and Birth Defects Foundation (6-FY03-071), National Institutes of Health (RO1 HD43997, 2RO1 HD061403, and R21 DE18031), Cleft Palate Foundation, and Alice Bohmfalk Trust to L.S. L.S. is a Hirschl Scholar.
PY - 2011/10/18
Y1 - 2011/10/18
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/80054744189
UR - https://www.scopus.com/pages/publications/80054744189#tab=citedBy
U2 - 10.1016/j.devcel.2011.08.005
DO - 10.1016/j.devcel.2011.08.005
M3 - Article
C2 - 21982646
AN - SCOPUS:80054744189
SN - 1534-5807
VL - 21
SP - 627
EP - 641
JO - Developmental cell
JF - Developmental cell
IS - 4
ER -