Regulation of lambdoid suture morphogenesis by Pdgfrα-dependent chondrocyte programs

Craniosynostosis is a congenital disorder caused by premature fusion of cranial sutures, fibrous joints that accommodate postnatal brain growth. Lambdoid synostosis, affecting the suture between the parietal and occipital bones, is among the rarest and most severe forms of the disease, yet its developmental etiology remains poorly understood. Although aberrant cartilage formation has been associated with lambdoid suture fusion, whether altered chondrocyte development is causative has not been directly tested. Here, we investigate the role of platelet-derived growth factor receptor alpha (PDGFRα) signaling in chondrocyte development and lambdoid suture morphogenesis. We show that mesoderm-specific expression of an autoactivated Pdgfra allele (Pdgfra+/K) results in premature fusion of both the lambdoid and occipitointerparietal sutures in mice, preceded by excessive expansion of cartilage adjacent to these sutures during embryogenesis. Using 10x Genomics spatial transcriptomics, we identify a PDGFRα-dependent transcriptional program marked by increased expression of Sox9, Sfrp2, and Col7a1, which cooperatively repress chondrocyte differentiation and maintain cells in a proliferative progenitor state. Consistent with these transcriptional changes, chondrocytes expressing activated PDGFRα exhibit elevated proliferative activity. Finally, chondrocyte-specific activation of Pdgfra+/Kselectively induces fusion of the occipitointerparietal suture, demonstrating that aberrant chondrocyte development is sufficient to drive craniosynostosis. Together, these findings define a developmental mechanism by which PDGFRα signaling sustains proliferative cartilage and disrupts normal suture patency, establishing dysregulated chondrocyte maturation as a causal contributor to lambdoid synostosis.