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Aberrantly activated Wnt/β‐catenin pathway co‐receptors LRP5 and LRP6 regulate osteoblast differentiation in the developing coronal sutures of an Apert syndrome ( Fgfr2 S252W /+ ) mouse model
Author(s) -
Min Swe Nay Myo,
Kobayashi Yukiho,
Kamimoto Hiroyuki,
Moriyama Keiji
Publication year - 2021
Publication title -
developmental dynamics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.634
H-Index - 141
eISSN - 1097-0177
pISSN - 1058-8388
DOI - 10.1002/dvdy.239
Subject(s) - wnt signaling pathway , lrp5 , lrp6 , biology , apert syndrome , frizzled , microbiology and biotechnology , catenin , signal transduction , craniosynostosis , genetics
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/β‐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 of Lrp5 and Lrp6 in CS of Fgfr2 S252W/+ mice, whereas both wild type (WT) and Fgfr2 S252W/+ mice showed similar expression of other Wnt/β‐catenin‐related genes, such as Wnt3 , Wnt3a , Fzd4 , Fzd6 , Axin2 , and Dkk1 as evidenced by in situ hybridization. Significantly increased Lrp5 and Lrp6 mRNA expression was observed by quantitative PCR analysis of cultured cells isolated from CS of Fgfr2 S252W/+ mice. Phospho‐LRP5, phospho‐LRP6, and non‐phospho‐β‐catenin were upregulated in Fgfr2 S252W/+ CS compared with that in WT CS. Short‐interfering RNA targeting Lrp5 and Lrp6 significantly 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/β‐catenin pathway was activated in the CS of Fgfr2 S252W/+ mice during craniofacial development, suggesting the involvement of the Wnt/β‐catenin pathway in the pathogenesis of CS synostosis in Fgfr2 S252W/+ mice.