Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-08, Vol.108 (31), p.12752-12757
• Main Authors: Barrott, Jared J, Cash, Gabriela M, Smith, Aaron P, Barrow, Jeffery R, Murtaugh, L. Charles
• Format: Article
• Language: English
• Subjects: Acyltransferases; alleles; Amino Acid Sequence; Animals; beta Catenin - genetics; beta Catenin - metabolism; Biological Sciences; Blotting, Western; Body Patterning - genetics; Cell lines; Cells, Cultured; Disease Models, Animal; Drosophila; Ectoderm - embryology; Ectoderm - metabolism; Embryo, Mammalian - cytology; Embryo, Mammalian - embryology; Embryo, Mammalian - metabolism; embryogenesis; Embryonic growth stage; Embryos; Etiology; Female; females; Fibroblasts - cytology; Fibroblasts - metabolism; Focal Dermal Hypoplasia - genetics; Focal Dermal Hypoplasia - metabolism; Gene Deletion; Genotype & phenotype; HeLa cells; heterozygosity; Humans; Hypoplasia; Insects; Ligands; Male; males; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; mutants; Mutation; patients; phenotype; Phenotypes; Porcupines; Proteins; Rodents; Secretion; Skin; Stem cells; TCF Transcription Factors - genetics; TCF Transcription Factors - metabolism; Wnt Proteins - genetics; Wnt Proteins - metabolism; Wnt-5a Protein; Wnt1 Protein - genetics; Wnt1 Protein - metabolism; Wnt3 Protein
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1006437108

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.