Dev Cell 21:627 (2011)
Elisabetta Ferretti, 1Bingsi Li,1Rediet Zewdu, 1Victoria Wells, 1Jean M. Hebert,2Courtney Karner,3 Matthew J. Anderson, 4Trevor Williams, 5Jill Dixon, 6Michael J. Dixon, 6Michael J. Depew,7and Licia Selleri1 ,*
Morphogenes is of mammalian facial processes requires coor dination of cellular proliferation, migration, and apoptos is 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 characteried 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. Dysre gulation 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.