RT Journal Article
SR Electronic
T1 Regulation of PDGFC signalling and extracellular matrix composition by FREM1 in mice
JF Disease Models & Mechanisms
JO Dis Models Mech
FD The Company of Biologists Limited
SP 1426
OP 1433
DO 10.1242/dmm.013748
VO 6
IS 6
A1 Wiradjaja, Fenny
A1 Cottle, Denny L.
A1 Jones, Lynelle
A1 Smyth, Ian
YR 2013
UL http://dmm.biologists.org/content/6/6/1426.abstract
AB 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.