Fzd7 Restrains Pink1-Dependent Mitophagy in Suture Stem Cells to Maintain Cranial Suture Patency

Craniosynostosis results from premature fusion of the cranial sutures, yet the contribution of suture mesenchymal stem cell (SuSC) dysfunction to this process remains incompletely understood. Here, we combined single-cell RNA-seq with 2-µm Visium HD spatial transcriptomics to define stage-specific changes in Prrx1⁺ SuSCs in the Fgfr2^C342Y/+ mouse model. We observed early downregulation of Frizzled-7 (Fzd7), increased mitophagy-associated signatures and readouts with elevated Pink1 expression, and premature osteogenic activation within the SuSC niche. In vitro, loss of Fzd7 increased mitophagy and osteogenic activity, whereas Fzd7 overexpression attenuated these changes. In vivo, conditional deletion of Fzd7 accelerated coronal suture fusion, while AAV-mediated Fzd7 overexpression reduced fusion. Conditional deletion of Pink1 suppressed the effects of Fzd7 loss, supporting Pink1-dependent mitophagy as a required component of the Fzd7-deficiency-associated osteogenic and fusion phenotypes. These findings support a model in which an Fzd7-Pink1 mitophagy axis contributes to the maintenance of suture patency in craniosynostosis and provide a mechanistic basis for future targeted studies.