Aberrantly activated Wnt/β-catenin pathway co-receptorsLRP5andLRP6regulate osteoblast differentiation in the developing coronal sutures of an Apert syndrome (Fgfr2S252W/+) mouse model

Background Apert syndrome is an autosomal, dominant inherited disorder characterized by craniosynostosis and syndactyly caused by gain-of-function mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. Wnt/beta-catenin signaling plays critical roles in regulating the skeletal development. Here, we analyzed the role of this pathway in the developing coronal sutures (CS) of a murine Apert syndrome model (Fgfr2(S252W/+)). Results We observed aberrantly increased mRNA expression ofLrp5andLrp6in CS ofFgfr2(S252W/+)mice, whereas both wild type (WT) andFgfr2(S252W/+)mice showed similar expression of other Wnt/beta-catenin-related genes, such asWnt3,Wnt3a,Fzd4,Fzd6,Axin2, andDkk1as evidenced by in situ hybridization. Significantly increasedLrp5andLrp6mRNA expression was observed by quantitative PCR analysis of cultured cells isolated from CS ofFgfr2(S252W/+)mice. Phospho-LRP5, phospho-LRP6, and non-phospho-beta-catenin were upregulated inFgfr2(S252W/+)CS compared with that in WT CS. Short-interfering RNA targetingLrp5andLrp6significantly reduced runt-related transcription factor 2, collagen type 1 alpha 1, and osteocalcin mRNA expression, and alkaline phosphatase activity in cultured cells. Conclusions The Wnt/beta-catenin pathway was activated in the CS ofFgfr2(S252W/+)mice during craniofacial development, suggesting the involvement of the Wnt/beta-catenin pathway in the pathogenesis of CS synostosis inFgfr2(S252W/+)mice.