Neural crest-specific deletion of <i>Rbfox2</i> in mice leads to craniofacial abnormalities including cleft palate.

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 <i>Rbfox2</i> 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 <i>Rbfox2</i> deletion. Furthermore, restoration of TGF-β signaling by Tak1 overexpression can rescue the proliferation defect seen in <i>Rbfox2</i> mutants. We also identified a positive <i>feedback loop</i> in which TGF-β signaling promotes expression of <i>Rbfox2</i> in NCCs.