Dev Cell 21: 627 (2011)

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

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.


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