Genetic investigation of Nogo and Nogo-66 receptor function: Focus on spinal cord injury.

摘要

Traumatic axonal injury in the adult mammalian central nervous system (CNS) normally results in loss of electrical conductance and significant functional deficits. Unlike peripheral neurons, central neurons fail to mount an adequate regenerative response once their axons are severed from their targets. This failure of regeneration of central axons is largely attributable to extrinsic factors present in the extracellular milieu of the CNS. Non-neuronal factors such as the astroglial scar and neurite outgrowth inhibitory molecules such as Nogo, myelin-associated glycoprotein (MAG), oligodendrocyte-myelin glycoprotein (OMgp), and chondroitin-sulfate proteoglycans (CSPG) are all implicated in restricting the regrowth of axons.; Nogo is a recently cloned member of the reticulon family of proteins that is expressed in CNS myelin and has been characterized as a potent inhibitor of neurite extension in vitro. In addition to a non-cell type-specific inhibitory domain near the amino terminus called Amino-Nogo, a 66-residue extracellular loop domain of Nogo (Nogo-66) signals growth cone collapse and neurite outgrowth inhibition via high-affinity interaction with a Nogo-66 receptor (NgR) found on axons.; Here, I have focused on the genetic investigations of the in vivo role of the Nogo/NgR system in axon regeneration. I show that ectopic overexpression of the shortest isoform of Nogo containing Nogo-66 in Schwann cells of the peripheral nervous system (PNS), results in a marked delay in peripheral axon regeneration and functional recovery in transgenic mice compared to wild type littermates, confirming the sufficiency of the loop domain in hindering neurite outgrowth in vivo. Furthermore, genetic manipulation of the Nogo and NgR loci allowed the generation of two knockout mouse lines. Both knockout lines were characterized and homozygotes were found to have enhanced axonal regeneration and functional recovery in models of spinal cord injury as compared to their heterozygotic or wild type littermates. Taken together, these findings strongly suggest that Nogo-66 and NgR have principal roles in limiting axon regeneration following CNS injury, and that interfering with their signaling may find beneficial clinical applications in a spectrum of neurological conditions, including spinal cord injury, brain trauma, and stroke. Further lines of inquiry into the phenotype of these knockout mice may shed new light into the normal physiological roles of Nogo-NgR interactions and help uncover caveats to potentially therapeutic but long-term strategies aimed at disrupting their function.