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Regulation of PDGFC signalling and extracellular matrix composition by FREM1 in mice
Fenny Wiradjaja1, Denny L Cottle, Lynelle Jones
1Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
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.
Insights
Fras1-related extracellular matrix protein 1 (FREM1) binds to PDGFC, regulating signaling and extracellular matrix remodeling. Loss of FREM1 function may cause Fraser syndrome by reducing PDGFC activity and impacting basement membrane integrity.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- Fras1-related extracellular matrix protein 1 (FREM1) is crucial for epidermal adhesion during embryonic development.
- Mutations in the FRAS/FREM gene family are linked to Fraser syndrome spectrum disorders.
- Embryonic epidermal blistering occurs in mice lacking PdgfC or its receptor, PDGFRα.
Purpose of the Study:
- To investigate the interaction between FREM1 and PDGFC.
- To elucidate the role of this interaction in PDGFRα signaling and extracellular matrix regulation.
- To understand the molecular mechanisms underlying epidermal blistering in Fraser syndrome.
Main Methods:
- Co-immunoprecipitation assays to detect FREM1-PDGFC binding.
- Analysis of PDGFC signaling in wild-type and Frem1-mutant fibroblasts.
- Assessment of Timp1 expression and collagen I deposition in response to PDGFC stimulation.
Main Results:
- FREM1 physically binds to PDGFC.
- Frem1-mutant fibroblasts exhibit altered PDGFC signaling duration and amplitude.
- PDGFC-stimulated Timp1 expression and basement membrane collagen I deposition are reduced in Frem1-mutant cells.
Conclusions:
- The interaction between FREM1 and PDGFC regulates extracellular matrix remodeling downstream of PDGFRα signaling.
- Loss of FREM1 function in Fraser syndrome may result from reduced PDGFC activity, contributing to epidermal blistering.
- FREM1 plays a dual role in epidermal development: stabilizing the basement membrane and modulating PDGFC signaling.
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