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.
- Manvendra K Singh
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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).
- Margaret Buckingham, CNRS UMR 3738, Institut Pasteur, France
© 2019, Cibi et al.
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