Craniofacial Development and Malformations research group, Orthodontics, Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.
Oral and Maxillofacial Diseases, Helsinki University Hospital, Helsinki, Finland.
Elife. 2020 Jul 14;9:e55829. doi: 10.7554/eLife.55829.
Mutations in the gene encoding () 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 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 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.
基因编码 () 的突变导致 Carpenter 综合征，其特征是多种发育异常，包括并指和颅骨形态发生缺陷。为了了解 RAB23 如何调节颅骨发育，我们生成了存活到骨骼发育可研究年龄的缺陷型小鼠。除了并指外，这些小鼠还表现出多个骨缝过早融合，这是由于异常的成骨前体细胞增殖和骨缝中骨生成增加所致。FGF10 驱动的 FGFR1 信号在骨缝中升高，导致 MAPK、Hedgehog 信号和 RUNX2 表达失衡。升高的 pERK1/2 信号的抑制导致成骨前体细胞增殖正常化，同时降低成骨基因表达，并预防颅缝早闭。我们的结果表明 RAB23 作为 FGFR 和经典 Hh-GLI1 信号的上游负调节剂具有新的作用，并且通过 pERK1/2 对 GLI1 进行非经典调节。
