Aberrantly activated Wnt/ß-catenin pathway co-receptors LRP5 and LRP6 regulate osteoblast differentiation in the developing coronal sutures of an Apert syndrome (Fgfr2S252W/+ ) mouse model.
Dev Dyn
; 250(3): 465-476, 2021 03.
Article
em En
| MEDLINE
| ID: mdl-32822074
ABSTRACT
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/ß-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 (Fgfr2S252W/+ ).RESULTS:
We observed aberrantly increased mRNA expression of Lrp5 and Lrp6 in CS of Fgfr2S252W/+ mice, whereas both wild type (WT) and Fgfr2S252W/+ mice showed similar expression of other Wnt/ß-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 Fgfr2S252W/+ mice. Phospho-LRP5, phospho-LRP6, and non-phospho-ß-catenin were upregulated in Fgfr2S252W/+ 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/ß-catenin pathway was activated in the CS of Fgfr2S252W/+ mice during craniofacial development, suggesting the involvement of the Wnt/ß-catenin pathway in the pathogenesis of CS synostosis in Fgfr2S252W/+ mice.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Osteoblastos
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Acrocefalossindactilia
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Diferenciação Celular
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Mutação de Sentido Incorreto
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Suturas Cranianas
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Receptor Tipo 2 de Fator de Crescimento de Fibroblastos
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Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade
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Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade
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Via de Sinalização Wnt
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Dev Dyn
Assunto da revista:
ANATOMIA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Japão