Fig. 4.

Summary model of FREM1 bat mutant basement membrane fragility. (Left) In WT mice, FREM1 forms a stabilising complex (1) with FRAS/FREM proteins to cross-link the lamina densa with the underlying dermis. Additionally, FREM1 binds keratinocyte-secreted PDGFC, which is presented to PDGFRα in the adjacent dermal fibroblasts, potentiating PDGFRα signalling and promoting ECM modelling events, including TIMP1 upregulation and COL1 deposition (2). (Right) In bat mice, FREM1 mutation removes the structural cross-link of the FRAS/FREM complex (1), but also reduces PDGFRα signalling, leading to lowered TIMP1 and diminished COL1 deposition (2), thereby further weakening part of the foundation of the basement membrane.