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

Abstract

Mutations in the gene encoding Ras-associated binding protein 23 (RAB23) cause Carpenter Syndrome, which is characterized by multiple developmental abnormalities including polysyndactyly and defects in skull morphogenesis. To understand how RAB23 regulates skull development, we generated Rab23-deficient mice that survive to an age where skeletal development can be studied. Along with polysyndactyly, these mice exhibit premature fusion of multiple sutures resultant from aberrant osteoprogenitor proliferation and elevated osteogenesis in the suture. FGF10-driven FGFR1 signaling is elevated in Rab23-/-sutures with a consequent imbalance in MAPK, Hedgehog signaling and RUNX2 expression. Inhibition of elevated pERK1/2 signaling results in the normalization of osteoprogenitor proliferation with a concomitant reduction of osteogenic gene expression, and prevention of craniosynostosis. Our results suggest a novel role for RAB23 as an upstream negative regulator of both FGFR and canonical Hh-GLI1 signaling, and additionally in the non-canonical regulation of GLI1 through pERK1/2.

• Authors: Md Rakibul Hasan, Maarit Takatalo, Hongqiang Ma, Ritva Rice, Tuija Mustonen, David Pc Rice
• Journal: eLife (Elife) Vol. 9 (07 14 2020) ISSN: 2050-084X [Electronic] England
• PMID: 32662771 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020, Hasan et al.

Chemical References

• Fgf10 protein, mouse
• Fibroblast Growth Factor 10
• Gli1 protein, mouse
• Zinc Finger Protein GLI1
• Rab23 protein, mouse
• rab GTP-Binding Proteins

Topics

• Animals
• Embryo, Mammalian (embryology)
• Fibroblast Growth Factor 10 (physiology)
• MAP Kinase Signaling System (physiology)
• Mice (embryology)
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Osteogenesis (genetics)
• Zinc Finger Protein GLI1 (physiology)
• rab GTP-Binding Proteins (genetics, metabolism)