GPR124/WNT signaling regulates hyaloid blood vessel regression and endothelial-mesenchymal transition

WNT signaling in endothelial cells is critical for physiological regression of hyaloid blood vessels during eye development, yet the specific WNT receptors and mechanisms involved remain elusive. Here, we identify GPR124, a known WNT7 co-receptor in brain endothelial cells, as a key regulator of hyaloid vessel regression. Endothelial-specific Gpr124 knockout mice exhibited impaired hyaloid vessel involution, which was fully rescued by pharmacological activation of the WNT pathway, indicating that GPR124 mediates WNT signaling in hyaloid endothelial cells as it does in brain endothelial cells. In contrast to previous studies suggesting that WNT signaling induces localized apoptosis in hyaloid endothelial cells leading to vessel occlusion, blood flow stasis, and secondary apoptosis of affected vascular segments, we observed GPR124/WNT-dependent apoptosis across entire vascular segments without evidence of initiating apoptotic events. To elucidate the mechanisms of GPR124/WNT-mediated hyaloid vessel regression, we performed single-cell RNA sequencing, revealing upregulation of WNT and TGFβ target genes in hyaloid endothelial cells, accompanied by partial endothelial-mesenchymal transition (EndMT). We propose that GPR124/WNT signaling mediates hyaloid vessel regression by inducing partial EndMT rather than direct apoptosis. These findings provide novel insights into the mechanisms of hyaloid vessel regression and expand the known vascular functions of GPR124 beyond the brain.