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Deletion of Porcn in mice leads to multiple developmental defects and models human focal dermal hypoplasia (Goltz syndrome).
- Source :
-
PloS one [PLoS One] 2012; Vol. 7 (3), pp. e32331. Date of Electronic Publication: 2012 Mar 06. - Publication Year :
- 2012
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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.<br />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.<br />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.
- Subjects :
- Acyltransferases
Animals
Breeding
Cell Line
Chimera
Focal Dermal Hypoplasia metabolism
Gene Expression Profiling
Gene Expression Regulation, Developmental
Gene Knockout Techniques
Gene Silencing
Gene Targeting
Genes, Lethal
Humans
Introns
Membrane Proteins metabolism
Mice, Inbred C57BL
Mice, Knockout
Phenotype
Wnt3A Protein metabolism
Zygote metabolism
Disease Models, Animal
Focal Dermal Hypoplasia genetics
Gene Deletion
Membrane Proteins genetics
Mice
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 7
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 22412863
- Full Text :
- https://doi.org/10.1371/journal.pone.0032331