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

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.

Pubmed ID: 21768372


  • Barrott JJ
  • Cash GM
  • Smith AP
  • Barrow JR
  • Murtaugh LC


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

August 2, 2011

Associated Grants

  • Agency: NIDDK NIH HHS, Id: R01 DK075072
  • Agency: NIDDK NIH HHS, Id: R01 DK075072-05
  • Agency: NIDDK NIH HHS, Id: R01-DK075072
  • Agency: NICHD NIH HHS, Id: R15-HD060087

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • Body Patterning
  • Cells, Cultured
  • Disease Models, Animal
  • Ectoderm
  • Embryo, Mammalian
  • Female
  • Fibroblasts
  • Focal Dermal Hypoplasia
  • Gene Deletion
  • Humans
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • TCF Transcription Factors
  • Wnt Proteins
  • Wnt1 Protein
  • Wnt3 Protein
  • beta Catenin