title: Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome.
abstract: The Drosophila porcupine gene is required for secretion of wingless and other Wnt proteins, and sporadic mutations in its unique human ortholog, PORCN, cause a pleiotropic X-linked dominant disorder, focal dermal hypoplasia (FDH, also known as Goltz syndrome). We generated a conditional allele of the X-linked mouse Porcn gene and analyzed its requirement in Wnt signaling and embryonic development. We find that Porcn-deficient cells exhibit a cell-autonomous defect in Wnt ligand secretion but remain responsive to exogenous Wnts. Consistent with the female-specific inheritance pattern of FDH, Porcn hemizygous male embryos arrest during early embryogenesis and fail to generate mesoderm, a phenotype previously associated with loss of Wnt activity. Heterozygous Porcn mutant females exhibit a spectrum of limb, skin, and body patterning abnormalities resembling those observed in human patients with FDH. Many of these defects are recapitulated by ectoderm-specific deletion of Porcn, substantiating a long-standing hypothesis regarding the etiology of human FDH and extending previous studies that have focused on downstream elements of Wnt signaling, such as β-catenin. Conditional deletion of Porcn thus provides an experimental model of FDH, as well as a valuable tool to probe Wnt ligand function in vivo.
authors.affiliation: Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Barrott
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Cash
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Smith
authors.forename: Jeffery R
authors.initials: JR
authors.lastname: Barrow
authors.forename: L Charles
authors.initials: LC
authors.lastname: Murtaugh
mesh_terms: D000217:Acyltransferases; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D019521:Body Patterning / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004475:Ectoderm / Q000196:embryology / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005489:Focal Dermal Hypoplasia / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D000071818:Wnt-5a Protein; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism; D060508:Wnt3 Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D060508:Wnt3 Protein; C438615:Wnt5a protein, mouse; D051176:beta Catenin; D000217:Acyltransferases; C491187:Porcn protein, mouse