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

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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 non-canonical regulation of GLI1. RAB23 regulates GLI1 through pERK1/2.

Data availability

MIAME-compliant microarray data has been deposited in GEO database. GEO accession GSE140884The dataset link: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE140884

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Md Rakibul Hasan

Oral and maxillofacial diseases, University of Helsinki, Helsinki, Finland

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5477-6934
Maarit Takatalo

Oral and maxillofacial diseases, University of Helsinki, Helsinki, Finland

Competing interests
The authors declare that no competing interests exist.
Hongqiang Ma

Oral and maxillofacial diseases, University of Helsinki, Helsinki, Finland

Competing interests
The authors declare that no competing interests exist.
Ritva Rice

Oral and maxillofacial diseases, University of Helsinki, University of Helsinki, Finland

Competing interests
The authors declare that no competing interests exist.
Tuija Mustonen

Developmental Biology Program, University of Helsinki, Helsinki, Finland

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2429-5064
David PC Rice

Oral and maxillofacial diseases, University of Helsinki, Helsinki, Finland

For correspondence
david.rice@helsinki.fi

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9301-3078

Funding

Suomen Akatemia (257472)

David PC Rice

Sigrid Juséliuksen Säätiö (4702957)

David PC Rice

The funders supported to perform this research.

Ethics

Animal experimentation: Animal experiments were approved by the University of Helsinki, Helsinki University Hospital and the Southern Finland Council Animal Welfare and Ethics committees. Permit ESAVI/11956/04.10.07/2017 (external) and KEK17-008 (internal).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.