RTN4RL1 (also known as NgR3) encodes a cell surface receptor that plays a critical role in central nervous system development and axon regeneration inhibition. The protein functions as a receptor for chondroitin sulfate proteoglycans (CSPGs), which are major inhibitors of axonal regeneration in the adult CNS 1. RTN4RL1 works redundantly with other Nogo receptor family members, particularly NgR1, to restrict axon regeneration following injury - triple knockout mice lacking all three Nogo receptors show enhanced axonal regeneration after optic nerve crush injury 1. During brain development, RTN4RL1 contributes to normal axon migration across the brain midline and corpus callosum formation, while also restricting dendritic spine and synapse formation 2. The protein mediates its inhibitory effects through Rho activation and actin cytoskeleton reorganization 2. Clinically, RTN4RL1 haploinsufficiency due to 17p13.3 microdeletions is associated with distinctive leukoencephalopathy characterized by multifocal white matter lesions 3. Patients with deletions encompassing RTN4RL1 present with developmental delay, intellectual disability, and characteristic brain imaging abnormalities 4. The gene is also expressed in immune cells, particularly B-cells during neuroinflammation, where it may contribute to inflammatory responses in conditions like experimental autoimmune encephalomyelitis 5.