Regulation of lambdoid suture morphogenesis by PDGFRα-dependent chondrocyte programs.

Craniosynostosis is a congenital disorder characterized by premature fusion of cranial sutures. Lambdoid synostosis is a rare and severe form of the disease, but its developmental etiology remains poorly understood. Although ectopic cartilage has been associated with lambdoid suture fusion, whether abnormal chondrocyte development is causative has not been directly tested. Here, we have investigated the role of platelet-derived growth factor receptor alpha (PDGFRα) signaling in chondrocyte development and lambdoid suture morphogenesis. Mesoderm-specific expression of an autoactivated Pdgfra allele (Pdgfra+/K) caused premature fusion of the lambdoid and occipitointerparietal sutures, preceded by excessive cartilage expansion during embryogenesis. Spatial transcriptomic analysis identified a PDGFRα-dependent transcriptional program characterized by increased Col2a1, Sox9 and Sfrp2 expression, indicating maintenance of chondrocytes in a proliferative progenitor state. Consistent with this, PDGFRα-activated chondrocytes exhibited increased proliferation. Moreover, expression of Pdgfra+/K in the Col2a1Cre lineage selectively induced occipitointerparietal suture fusion. Together, these findings demonstrate that PDGFRα signaling promotes proliferative cartilage and impairs chondrocyte maturation, identifying dysregulated chondrogenesis as a developmental mechanism underlying lambdoid craniosynostosis.