GPR124 regulates hyaloid blood vessel regression and is associated with endothelial-mesenchymal transition

Transition from the transient hyaloid vasculature to the mature retinal vascular network is a critical step in mammalian eye development. While WNT7B signaling in endothelial cells regulates programmed hyaloid vessel regression, the specific receptors and downstream mechanisms remain poorly defined. Here, we identify GPR124, a ligand-specific co-receptor for WNT7A/B, as a key regulator of this process. Using an endothelial-specific, tamoxifen-inducible Gpr124 knockout mouse model, we show that loss of GPR124 in hyaloid endothelium markedly impairs postnatal hyaloid vessel clearance. Notably, GPR124 function in the developing eye was highly compartment-specific: although crucial for hyaloid vessel regression, it was dispensable for retinal angiogenesis, despite being expressed in both vascular beds. Gpr124 deletion led to downregulation of several established WNT target genes in hyaloid endothelial cells, consistent with a role for GPR124 in mediating WNT/β-catenin signaling, as previously shown in brain endothelium. While GPR124 was not required for induction of isolated apoptotic events in hyaloid vessels, it promoted segmental vessel regression, characterized by linear clusters of apoptotic endothelial cells. Single-cell RNA sequencing of hyaloid endothelial cells, combined with immunostaining, revealed transcriptional changes consistent with partial endothelial-mesenchymal transition (EndMT). Our findings identify GPR124 as a key mediator of hyaloid vessel regression and suggest that GPR124-dependent WNT/β-catenin signaling and EndMT may contribute to vascular remodeling during ocular development.