Regulation of PDGFC signalling and extracellular matrix composition by FREM1 in mice
SUMMARY 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 syndr...
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The Company of Biologists
2013-11-01
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Series: | Disease Models & Mechanisms |
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doaj-a19c57f8c4fd44e08e233085e5a3ecb62020-11-25T02:21:37ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112013-11-01661426143310.1242/dmm.013748013748Regulation of PDGFC signalling and extracellular matrix composition by FREM1 in miceFenny WiradjajaDenny L. CottleLynelle JonesIan SmythSUMMARY 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.http://dmm.biologists.org/content/6/6/1426 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Fenny Wiradjaja Denny L. Cottle Lynelle Jones Ian Smyth |
spellingShingle |
Fenny Wiradjaja Denny L. Cottle Lynelle Jones Ian Smyth Regulation of PDGFC signalling and extracellular matrix composition by FREM1 in mice Disease Models & Mechanisms |
author_facet |
Fenny Wiradjaja Denny L. Cottle Lynelle Jones Ian Smyth |
author_sort |
Fenny Wiradjaja |
title |
Regulation of PDGFC signalling and extracellular matrix composition by FREM1 in mice |
title_short |
Regulation of PDGFC signalling and extracellular matrix composition by FREM1 in mice |
title_full |
Regulation of PDGFC signalling and extracellular matrix composition by FREM1 in mice |
title_fullStr |
Regulation of PDGFC signalling and extracellular matrix composition by FREM1 in mice |
title_full_unstemmed |
Regulation of PDGFC signalling and extracellular matrix composition by FREM1 in mice |
title_sort |
regulation of pdgfc signalling and extracellular matrix composition by frem1 in mice |
publisher |
The Company of Biologists |
series |
Disease Models & Mechanisms |
issn |
1754-8403 1754-8411 |
publishDate |
2013-11-01 |
description |
SUMMARY
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. |
url |
http://dmm.biologists.org/content/6/6/1426 |
work_keys_str_mv |
AT fennywiradjaja regulationofpdgfcsignallingandextracellularmatrixcompositionbyfrem1inmice AT dennylcottle regulationofpdgfcsignallingandextracellularmatrixcompositionbyfrem1inmice AT lynellejones regulationofpdgfcsignallingandextracellularmatrixcompositionbyfrem1inmice AT iansmyth regulationofpdgfcsignallingandextracellularmatrixcompositionbyfrem1inmice |
_version_ |
1724865184432914432 |