title: A conserved Pbx-Wnt-p63-Irf6 regulatory module controls face morphogenesis by promoting epithelial apoptosis.
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.
authors: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors: Elisabetta
authors: E
authors: Ferretti
authors: Bingsi
authors: B
authors: Li
authors: Rediet
authors: R
authors: Zewdu
authors: Victoria
authors: V
authors: Wells
authors: Jean M
authors: JM
authors: Hebert
authors: Courtney
authors: C
authors: Karner
authors: Matthew J
authors: MJ
authors: Anderson
authors: Trevor
authors: T
authors: Williams
authors: Jill
authors: J
authors: Dixon
authors: Michael J
authors: MJ
authors: Dixon
authors: Michael J
authors: MJ
authors: Depew
authors: Licia
authors: L
authors: Selleri
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D015153:Blotting, Western; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D002971:Cleft Lip / Q000196:embryology / Q000378:metabolism; D002972:Cleft Palate / Q000196:embryology / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004847:Epithelial Cells / Q000378:metabolism*; D005145:Face / Q000196:embryology*; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D007124:Immunoenzyme Techniques; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000502:physiology; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000502:physiology*; D014162:Transfection; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; C528250:IRF6 protein, mouse; D050835:Interferon Regulatory Factors; C481797:Pbx1 protein, mouse; D010750:Phosphoproteins; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse; D051153:Wnt Proteins; D060508:Wnt3 Protein; C555508:Wnt3 protein, mouse; C515303:Wnt9b protein, mouse; D008156:Luciferases