Srsf3 mediates alternative RNA splicing downstream of PDGFRα signaling in the facial mesenchyme

Signaling through the platelet-derived growth factor receptor alpha (PDGFR alpha) is crucial for mammalian craniofacial development, although 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 PDGFR alpha signaling in mouse palatal mesenchyme cells, leading to its nuclear translocation. We further demonstrate that ablation of Srsf3 in the mouse neural crest lineage leads to facial clefting due to defective cranial neural crest cell proliferation and survival. Finally, we show that Srsf3 regulates the alternative RNA splicing of transcripts encoding protein kinases in the mouse facial process mesenchyme to regulate PDGFR alpha-dependent intracellular signaling. Collectively, our findings reveal that alternative RNA splicing is an important mechanism of gene expression regulation downstream of PI3K/Akt-mediated PDGFR alpha signaling in the facial mesenchyme and identify Srsf3 as a critical regulator of craniofacial development.

Automated summary

Signaling through PDGFR alpha is important for craniofacial development, and this study reveals that Srsf3, phosphorylated downstream of PI3K-mediated signaling, plays a critical role in regulating gene expression changes and neural crest cell proliferation. The ablation of Srsf3 in mouse neural crest lineage leads to facial clefting, highlighting the significance of alternative RNA splicing in PDGFR alpha-dependent intracellular signaling in craniofacial development.