title: Regulation of PDGFC signalling and extracellular matrix composition by FREM1 in mice.
abstract: Fras1-related extracellular matrix protein 1 (FREM1) is required for epidermal adhesion during embryogenesis, and mice lacking the gene develop fetal skin blisters and a range of other developmental defects. Mutations in members of the FRAS/FREM gene family cause diseases of the Fraser syndrome spectrum. Embryonic epidermal blistering is also observed in mice lacking PdgfC and its receptor, PDGFRα. In this article, we show that FREM1 binds to PDGFC and that this interaction regulates signalling downstream of PDGFRα. Fibroblasts from Frem1-mutant mice respond to PDGFC stimulation, but with a shorter duration and amplitude than do wild-type cells. Significantly, PDGFC-stimulated expression of the metalloproteinase inhibitor Timp1 is reduced in cells with Frem1 mutations, leading to reduced basement membrane collagen I deposition. These results show that the physical interaction of FREM1 with PDGFC can regulate remodelling of the extracellular matrix downstream of PDGFRα. We propose that loss of FREM1 function promotes epidermal blistering in Fraser syndrome as a consequence of reduced PDGFC activity, in addition to its stabilising role in the basement membrane.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors.forename: Fenny
authors.initials: F
authors.lastname: Wiradjaja
authors.forename: Denny L
authors.initials: DL
authors.lastname: Cottle
authors.forename: Lynelle
authors.initials: L
authors.lastname: Jones
authors.forename: Ian
authors.initials: I
authors.lastname: Smyth
mesh_terms: D000818:Animals; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism / Q000502:physiology*; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016326:Extracellular Matrix Proteins; C492585:Frem1 protein, mouse; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; C411423:platelet-derived growth factor C
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