Reticulon 4
Protein-coding gene in humans
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Reticulon 4, also known as Neurite outgrowth inhibitor or Nogo, is a protein that in humans is encoded by the RTN4 gene.[5][6][7] It belongs to the family of reticulon-encoding genes, whose members are associated with the endoplasmic reticulum and participate in neuroendocrine secretion and membrane trafficking in neuroendocrine cells. The product of this gene is a potent inhibitor of neurite outgrowth and is thought to contribute to the limited regenerative capacity of the central nervous system in higher vertebrates.[7]
Structure
Alternatively spliced transcript variants derived from both differential splicing and differential promoter usage have been identified and encode distinct isoforms of Nogo.[7] There are three known isoforms: Nogo-A, Nogo-B, and Nogo-C.
Nogo-A contains two characterized inhibitory domains: amino-Nogo at the N-terminus and Nogo-66, which forms the molecule's extracellular loop. Both domains participate in inhibitory signaling. Amino-Nogo acts as a strong inhibitor of neurite outgrowth, whereas Nogo-66 is involved in growth cone destruction.[8]
Function
Nogo has been identified as an inhibitor of neurite outgrowth specific to the central nervous system.[5][6]
During neural development, Nogo is expressed mainly by neurons and provides an inhibitory signal for the migration and sprouting of CNS endothelial (tip) cells, thereby restricting blood vessel density.
Nogo also has functions beyond axonal growth inhibition. It has been identified as a key mediator in the process through which physical exercise enhances learning and memory in the brain.[9]
Nogo-A has additionally been shown to negatively regulate vascular growth and repair following ischemic stroke. Genetic deletion and antibody-mediated blockade of Nogo-A enhanced revascularization and functional recovery in an experimental mouse model of stroke.[10][11][12]
Clinical significance
Because Nogo inhibits neurite regeneration, it has been investigated as a therapeutic target for nervous system repair. Research suggests that blocking Nogo-A following neuronal injury, including damage associated with diseases such as multiple sclerosis, may promote protection or restoration of injured neurons.[8][13]
Investigation into the mechanisms of this protein has generated interest for the treatment of auto-immune mediated demyelinating diseases and spinal cord injury regeneration.
Following ischemic stroke, treatment with anti-Nogo-A antibodies was also found to reduce vascular leakage, a major complication associated with post-stroke tissue injury.[14]