RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1

Area of Science:

• Developmental biology
• Genetics
• Molecular biology

Background:

• Mutations in Ras-associated binding protein 23 (RAB23) are linked to Carpenter Syndrome, a condition featuring developmental abnormalities like polysyndactyly and skull defects.
• Understanding RAB23's role in skull development is crucial for addressing related congenital disorders.

Purpose of the Study:

• To investigate the function of RAB23 in skull development using a mouse model.
• To elucidate the molecular mechanisms by which RAB23 regulates osteogenesis and suture development.

Main Methods:

• Generation and analysis of Rab23-deficient mice.
• Assessment of skeletal development, including polysyndactyly and craniosynostosis.
• Molecular analysis of signaling pathways (FGF/MAPK, Hedgehog) and gene expression (RUNX2) in skull sutures.
• Pharmacological inhibition of pERK1/2 signaling.

Main Results:

• Rab23-deficient mice displayed polysyndactyly and premature fusion of skull sutures due to increased osteoprogenitor proliferation and osteogenesis.
• Elevated FGF10-driven FGFR1 signaling, MAPK, Hedgehog signaling, and RUNX2 expression were observed in Rab23-deficient sutures.
• Inhibition of elevated pERK1/2 signaling normalized osteoprogenitor proliferation, reduced osteogenic gene expression, and prevented craniosynostosis.

Conclusions:

• RAB23 acts as a novel upstream negative regulator of both FGFR and canonical Hedgehog-GLI1 signaling.
• RAB23 also participates in the non-canonical regulation of GLI1 through pERK1/2 signaling.
• Targeting RAB23-mediated signaling pathways may offer therapeutic strategies for craniosynostosis and related developmental disorders.