CELSR2 (cadherin EGF LAG seven-pass G-type receptor 2), also known as ADGRC2, is an adhesion G protein-coupled receptor with critical roles in nervous system development and axon regeneration. 1 CELSR2 functions as a seven-transmembrane receptor involved in cell-cell signaling, with established roles in ciliogenesis and neural development, including neuron migration and axon guidance. 2 The receptor engages GαS G proteins through multiple activation mechanisms, including both autoproteolytic cleavage-dependent and cleavage-independent pathways. 3 Mechanistically, CELSR2 negatively regulates motor axon regeneration; its inactivation promotes axon fasciculation and regeneration in cultured spinal explants and intact mice following brachial plexus injury, accompanied by increased GTP-bound Rac1 and Cdc42 levels and elevated JNK/c-Jun signaling. 4 CELSR2 has been identified as a receptor for the p53-regulated protein Reprimo, which induces apoptosis through the Hippo-YAP/TAZ-p73 pathway, implicating CELSR2 in tumor suppression. 5 Clinically, CELSR2 variants are associated with calcific aortic stenosis risk across multiple ancestry groups, with genome-wide significant associations identified in large multiancestry cohorts. 6 7 CELSR2 has also been identified as a candidate gene in ciliopathies, including potential involvement in Meckel-Gruber syndrome. 8