Srsf3 mediates alternative RNA splicing downstream of PDGFRα signaling.

Signaling through the platelet-derived growth factor receptor alpha (PDGFRa) is critical for mammalian craniofacial development, though the mechanisms by which the activity of downstream intracellular effectors is regulated to mediate gene expression changes have not been defined. We find that the RNA-binding protein Srsf3 is phosphorylated at Akt consensus sites downstream of PI3K-mediated PDGFRa signaling in palatal mesenchyme cells, leading to its nuclear translocation. We further demonstrate that ablation of Srsf3 in the neural crest lineage leads to facial clefting due to defective cranial neural crest cell specification and survival. Finally, we show that Srsf3 regulates the alternative RNA splicing of transcripts encoding protein kinases in the facial process mesenchyme to negatively regulate PDGFRa signaling. Collectively, our findings reveal that PI3K/Akt-mediated PDGFRa signaling primarily modulates gene expression through alternative RNA splicing in the facial mesenchyme and identify Srsf3 as a critical regulator of craniofacial development. mRNA profiles from three biological replicates each of mouse Pdgfra+/+ versus PdgfraPI3K/PI3K E13.5 palatal shelf mesenchyme and Srsf3fl/fl;Wnt1-Cre+/+ versus Srsf3fl/fl;Wnt1-Cre+/Tg E11.5 maxillary process mesenchyme