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.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis*
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Base Sequence
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Blotting, Western
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Cell Proliferation
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Chromatin Immunoprecipitation
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Cleft Lip / embryology
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Cleft Lip / metabolism
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Cleft Palate / embryology
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Cleft Palate / metabolism
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Electrophoretic Mobility Shift Assay
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Epithelial Cells / metabolism*
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Face / embryology*
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Homeodomain Proteins / physiology*
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Humans
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Immunoenzyme Techniques
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Interferon Regulatory Factors / genetics
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Interferon Regulatory Factors / metabolism*
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Luciferases / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Molecular Sequence Data
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Morphogenesis / physiology
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Phenotype
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Pre-B-Cell Leukemia Transcription Factor 1
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RNA, Messenger / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Homology, Nucleic Acid
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcription Factors / physiology*
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Transfection
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Wnt Proteins / genetics
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Wnt Proteins / metabolism*
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Wnt3 Protein / genetics
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Wnt3 Protein / metabolism*
Substances
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Homeodomain Proteins
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IRF6 protein, mouse
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Interferon Regulatory Factors
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Pbx1 protein, mouse
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Phosphoproteins
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Pre-B-Cell Leukemia Transcription Factor 1
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RNA, Messenger
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Trans-Activators
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Transcription Factors
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Trp63 protein, mouse
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Wnt Proteins
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Wnt3 Protein
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Wnt3 protein, mouse
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Wnt9b protein, mouse
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Luciferases