Additive effects on craniofacial development upon conditional ablation of PDGFRα and SHP2 in the mouse neural crest lineage.

BACKGROUND: Activity of the receptor tyrosine kinase PDGFRα and the tyrosine phosphatase SHP2 are critical for vertebrate craniofacial development. We sought to determine the effect of SHP2 binding to PDGFRα via phenotypic and biochemical analyses of an allelic series of mouse embryos with combined loss of both proteins in the neural crest lineage. RESULTS: We demonstrated that SHP2 preferentially binds PDGFRα/α homodimers among the three PDGFR dimers. Analysis of allelic series mutant embryos revealed increased cell death in the lateral nasal and maxillary processes at E10.5, variably penetrant facial blebbing, facial hemorrhaging, midline clefting and loss of the mandibular region at E13.5, and widespread craniofacial bone and cartilage defects at birth. Further, we showed that loss of SHP2 leads to increased phosphorylation of PDGFRα and the downstream effector Erk1/2 in E10.5 allelic series mutant embryo lysates. CONCLUSIONS: Together, our findings demonstrate additive effects on craniofacial development upon conditional ablation of PDGFRα and SHP2 in the mouse neural crest lineage and indicate that SHP2 may negatively and positively regulate PDGFRα signaling through distinct mechanisms.