title: Deletion of Porcn in mice leads to multiple developmental defects and models human focal dermal hypoplasia (Goltz syndrome).
abstract: BACKGROUND
  Focal Dermal Hypoplasia (FDH) is a genetic disorder characterized by developmental defects in skin, skeleton and ectodermal appendages. FDH is caused by dominant loss-of-function mutations in X-linked PORCN. PORCN orthologues in Drosophila and mice encode endoplasmic reticulum proteins required for secretion and function of Wnt proteins. Wnt proteins play important roles in embryo development, tissue homeostasis and stem cell maintenance. Since features of FDH overlap with those seen in mouse Wnt pathway mutants, FDH likely results from defective Wnt signaling but molecular mechanisms by which inactivation of PORCN affects Wnt signaling and manifestations of FDH remain to be elucidated.
  
  
  RESULTS
  We introduced intronic loxP sites and a neomycin gene in the mouse Porcn locus for conditional inactivation. Porcn-ex3-7flox mice have no apparent developmental defects, but chimeric mice retaining the neomycin gene (Porcn-ex3-7Neo-flox) have limb, skin, and urogenital abnormalities. Conditional Porcn inactivation by EIIa-driven or Hprt-driven Cre recombinase results in increased early embryonic lethality. Mesenchyme-specific Prx-Cre-driven inactivation of Porcn produces FDH-like limb defects, while ectodermal Krt14-Cre-driven inactivation produces thin skin, alopecia, and abnormal dentition. Furthermore, cell-based assays confirm that human PORCN mutations reduce WNT3A secretion.
  
  
  CONCLUSIONS
  These data indicate that Porcn inactivation in the mouse produces a model for human FDH and that phenotypic features result from defective WNT signaling in ectodermal- and mesenchymal-derived structures.
authors.affiliation: Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Shaver
authors.forename: Alfred
authors.initials: A
authors.lastname: Balasa
authors.forename: M Cecilia
authors.initials: MC
authors.lastname: Ljungberg
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Wang
authors.forename: Shu
authors.initials: S
authors.lastname: Wen
authors.forename: Hoang
authors.initials: H
authors.lastname: Nguyen
authors.forename: Ignatia B
authors.initials: IB
authors.lastname: Van den Veyver
mesh_terms: D000217:Acyltransferases; D000818:Animals; D001947:Breeding; D002460:Cell Line; D002678:Chimera; D004195:Disease Models, Animal; D005489:Focal Dermal Hypoplasia / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D020868:Gene Silencing; D018390:Gene Targeting; D005804:Genes, Lethal; D006801:Humans; D007438:Introns; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D060509:Wnt3A Protein / Q000378:metabolism; D015053:Zygote / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D060509:Wnt3A Protein; D000217:Acyltransferases; C491187:Porcn protein, mouse