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 RIS Download
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 | Wnt-5a Protein | Wnt1 Protein | Wnt3 Protein | beta Catenin