RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1
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-defic...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2020-07-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/55829 |
| _version_ | 1811228125828218880 |
|---|---|
| author | Md Rakibul Hasan Maarit Takatalo Hongqiang Ma Ritva Rice Tuija Mustonen David PC Rice |
| author_facet | Md Rakibul Hasan Maarit Takatalo Hongqiang Ma Ritva Rice Tuija Mustonen David PC Rice |
| author_sort | Md Rakibul Hasan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T09:53:18Z |
| format | Article |
| id | doaj.art-72daf74273014ef79686e68218078f54 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:53:18Z |
| publishDate | 2020-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-72daf74273014ef79686e68218078f542022-12-22T03:37:47ZengeLife Sciences Publications LtdeLife2050-084X2020-07-01910.7554/eLife.55829RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1Md Rakibul Hasan0https://orcid.org/0000-0002-5477-6934Maarit Takatalo1Hongqiang Ma2Ritva Rice3Tuija Mustonen4https://orcid.org/0000-0002-2429-5064David PC Rice5https://orcid.org/0000-0001-9301-3078Craniofacial Development and Malformations research group, Orthodontics, Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, FinlandCraniofacial Development and Malformations research group, Orthodontics, Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, FinlandCraniofacial Development and Malformations research group, Orthodontics, Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, FinlandCraniofacial Development and Malformations research group, Orthodontics, Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, FinlandCraniofacial Development and Malformations research group, Orthodontics, Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, FinlandCraniofacial Development and Malformations research group, Orthodontics, Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland; Oral and Maxillofacial Diseases, Helsinki University Hospital, Helsinki, FinlandMutations 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.https://elifesciences.org/articles/55829RAB23CraniosynostosisMAPK signalingGLI1RUNX2 |
| spellingShingle | Md Rakibul Hasan Maarit Takatalo Hongqiang Ma Ritva Rice Tuija Mustonen David PC Rice RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1 eLife RAB23 Craniosynostosis MAPK signaling GLI1 RUNX2 |
| title | RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1 |
| title_full | RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1 |
| title_fullStr | RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1 |
| title_full_unstemmed | RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1 |
| title_short | RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1 |
| title_sort | rab23 coordinates early osteogenesis by repressing fgf10 perk1 2 and gli1 |
| topic | RAB23 Craniosynostosis MAPK signaling GLI1 RUNX2 |
| url | https://elifesciences.org/articles/55829 |
| work_keys_str_mv | AT mdrakibulhasan rab23coordinatesearlyosteogenesisbyrepressingfgf10perk12andgli1 AT maarittakatalo rab23coordinatesearlyosteogenesisbyrepressingfgf10perk12andgli1 AT hongqiangma rab23coordinatesearlyosteogenesisbyrepressingfgf10perk12andgli1 AT ritvarice rab23coordinatesearlyosteogenesisbyrepressingfgf10perk12andgli1 AT tuijamustonen rab23coordinatesearlyosteogenesisbyrepressingfgf10perk12andgli1 AT davidpcrice rab23coordinatesearlyosteogenesisbyrepressingfgf10perk12andgli1 |