RTN4RL2 (reticulon 4 receptor like 2) is a cell surface receptor belonging to the Nogo receptor family that mediates multiple aspects of neuronal development and immune regulation. As a functional homolog of NgR1 and NgR3, RTN4RL2 binds chondroitin sulfate proteoglycans (CSPGs) and myelin-associated inhibitors (MAIs) to restrict neurite outgrowth and axonal regeneration in the central nervous system 1. The receptor signals through Rho GTPase activation and downstream actin cytoskeleton reorganization to regulate dendritic spine formation and synapse number during brain development [PMID:22325200 from UniProt]. RTN4RL2 contributes to normal axon migration across the brain midline and corpus callosum formation, with functional redundancy among Nogo receptor family members such that triple mutants (Ngr1/Ngr2/Ngr3) are required for enhanced regeneration phenotypes 1. Clinically, RTN4RL2 emerges as a disease biomarker across multiple conditions. Plasma RTN4RL2 levels predict cognitive decline in language and visuospatial domains over 9-year follow-up in aging populations 2, and RTN4RL2 variants associate with Hodgkin lymphoma susceptibility (rs61745214, P=7.71×10⁻¹²) 3. RTN4RL2 is also differentially expressed in active-phase relapsing-remitting multiple sclerosis 4 and shows downregulation in hibernating bear kidneys, suggesting roles in metabolic and immunological adaptation 5. Additionally, NgR2 (RTN4RL2's structural homolog) promotes neuroendocrine differentiation in prostate cancer through αVβ3 integrin signaling 6, and RTN4RL2 expression on dendritic cells regulates their adhesion to myelin 7.