1. Developmental Biology
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Neural crest-specific deletion of Rbfox2 in mice leads to craniofacial abnormalities including cleft palate

  1. Dasan Mary Cibi
  2. Masum M Mia
  3. Shamini Guna Shekeran
  4. Lim Sze Yun
  5. Reddemma Sandireddy
  6. Priyanka Gupta
  7. Monalisa Hota
  8. Lei Sun
  9. Sujoy Ghosh
  10. Manvendra K Singh  Is a corresponding author
  1. Duke-NUS Medical School Singapore, Singapore
  2. National Heart Center Singapore, Singapore
Research Article
  • Cited 4
  • Views 2,088
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Cite this article as: eLife 2019;8:e45418 doi: 10.7554/eLife.45418
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Abstract

Alternative splicing (AS) creates proteomic diversity from a limited size genome by generating numerous transcripts from a single protein-coding gene. Tissue-specific regulators of AS are essential components of the gene regulatory network, required for normal cellular function, tissue patterning, and embryonic development. However, their cell-autonomous function in neural crest development has not been explored. Here, we demonstrate that splicing factor Rbfox2 is expressed in the neural crest cells (NCCs), and deletion of Rbfox2 in NCCs leads to cleft palate and defects in craniofacial bone development. RNA-Seq analysis revealed that Rbfox2 regulates splicing and expression of numerous genes essential for neural crest/craniofacial development. We demonstrate that Rbfox2-TGF-β-Tak1 signaling axis is deregulated by Rbfox2 deletion. Furthermore, restoration of TGF-β signaling by Tak1 overexpression can rescue the proliferation defect seen in Rbfox2 mutants. We also identified a positive feedback loop in which TGF-β signaling promotes expression of Rbfox2 in NCCs.

Data availability

RNA Sequencing data have been deposited in GEO under accession code GSE127245

The following data sets were generated

Article and author information

Author details

  1. Dasan Mary Cibi

    Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  2. Masum M Mia

    Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  3. Shamini Guna Shekeran

    Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  4. Lim Sze Yun

    National Heart Research Institute Singapore, National Heart Center Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  5. Reddemma Sandireddy

    Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  6. Priyanka Gupta

    Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  7. Monalisa Hota

    Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  8. Lei Sun

    Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3937-941X
  9. Sujoy Ghosh

    Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  10. Manvendra K Singh

    Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School Singapore, Singapore, Singapore
    For correspondence
    manvendra.singh@duke-nus.edu.sg
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2884-0074

Funding

National Research Foundation Singapore (NRF-NRFF2016-01)

  • Manvendra K Singh

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The Institutional Animal Care and Use Committee (IACUC) at SingHealth and Duke-NUS Medical School approved all the animal experiments (IACUC protocol number 2014/SHS/0988 and 2018/SHS/1415).

Reviewing Editor

  1. Margaret Buckingham, CNRS UMR 3738, Institut Pasteur, France

Publication history

  1. Received: January 23, 2019
  2. Accepted: June 25, 2019
  3. Accepted Manuscript published: June 26, 2019 (version 1)
  4. Version of Record published: July 29, 2019 (version 2)

Copyright

© 2019, Cibi 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.

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