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 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

Article and author information

Author details

  1. Md Rakibul Hasan

    Oral and maxillofacial diseases, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5477-6934
  2. Maarit Takatalo

    Oral and maxillofacial diseases, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  3. Hongqiang Ma

    Oral and maxillofacial diseases, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  4. Ritva Rice

    Oral and maxillofacial diseases, University of Helsinki, University of Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
  5. Tuija Mustonen

    Developmental Biology Program, University of Helsinki, Helsinki, Finland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2429-5064
  6. 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.
    ORCID icon "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).

Reviewing Editor

  1. Mone Zaidi, Icahn School of Medicine at Mount Sinai, United States

Publication history

  1. Received: February 6, 2020
  2. Accepted: July 13, 2020
  3. Accepted Manuscript published: July 14, 2020 (version 1)
  4. Version of Record published: August 12, 2020 (version 2)

Copyright

© 2020, Hasan et al.

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.

Metrics

  • 1,509
    Page views
  • 224
    Downloads
  • 7
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Md Rakibul Hasan
  2. Maarit Takatalo
  3. Hongqiang Ma
  4. Ritva Rice
  5. Tuija Mustonen
  6. David PC Rice
(2020)
RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1
eLife 9:e55829.
https://doi.org/10.7554/eLife.55829
  1. Further reading

Further reading

    1. Developmental Biology
    Yanling Xin, Qinghai He ... Shuyi Chen
    Research Article

    N 6-methyladenosine (m6A) is the most prevalent mRNA internal modification and has been shown to regulate the development, physiology, and pathology of various tissues. However, the functions of the m6A epitranscriptome in the visual system remain unclear. In this study, using a retina-specific conditional knockout mouse model, we show that retinas deficient in Mettl3, the core component of the m6A methyltransferase complex, exhibit structural and functional abnormalities beginning at the end of retinogenesis. Immunohistological and single-cell RNA sequencing (scRNA-seq) analyses of retinogenesis processes reveal that retinal progenitor cells (RPCs) and Müller glial cells are the two cell types primarily affected by Mettl3 deficiency. Integrative analyses of scRNA-seq and MeRIP-seq data suggest that m6A fine-tunes the transcriptomic transition from RPCs to Müller cells by promoting the degradation of RPC transcripts, the disruption of which leads to abnormalities in late retinogenesis and likely compromises the glial functions of Müller cells. Overexpression of m6A-regulated RPC transcripts in late RPCs partially recapitulates the Mettl3-deficient retinal phenotype. Collectively, our study reveals an epitranscriptomic mechanism governing progenitor-to-glial cell transition during late retinogenesis, which is essential for the homeostasis of the mature retina. The mechanism revealed in this study might also apply to other nervous systems.

    1. Developmental Biology
    2. Genetics and Genomics
    Xiaodong Li, Patrick J Gordon ... Edward M Levine
    Research Article

    An important question in organogenesis is how tissue-specific transcription factors interact with signaling pathways. In some cases, transcription factors define the context for how signaling pathways elicit tissue- or cell-specific responses, and in others, they influence signaling through transcriptional regulation of signaling components or accessory factors. We previously showed that during optic vesicle patterning, the Lim-homeodomain transcription factor Lhx2 has a contextual role by linking the Sonic Hedgehog (Shh) pathway to downstream targets without regulating the pathway itself. Here, we show that during early retinal neurogenesis in mice, Lhx2 is a multilevel regulator of Shh signaling. Specifically, Lhx2 acts cell autonomously to control the expression of pathway genes required for efficient activation and maintenance of signaling in retinal progenitor cells. The Shh co-receptors Cdon and Gas1 are candidate direct targets of Lhx2 that mediate pathway activation, whereas Lhx2 directly or indirectly promotes the expression of other pathway components important for activation and sustained signaling. We also provide genetic evidence suggesting that Lhx2 has a contextual role by linking the Shh pathway to downstream targets. Through these interactions, Lhx2 establishes the competence for Shh signaling in retinal progenitors and the context for the pathway to promote early retinal neurogenesis. The temporally distinct interactions between Lhx2 and the Shh pathway in retinal development illustrate how transcription factors and signaling pathways adapt to meet stage-dependent requirements of tissue formation.