Systemic Deletion of the Myelin-Associated Outgrowth Inhibitor Nogo-A Improves Regenerative and Plastic Responses after Spinal Cord Injury

Abstract

To investigate the role of the myelin-associated protein Nogo-A on axon sprouting and regeneration in the adult central nervous system (CNS), we generated Nogo-A-deficient mice. Nogo-A knockout (KO) mice were viable, fertile, and not obviously afflicted by major developmental or neurological disturbances. The shorter splice form Nogo-B was strongly upregulated in the CNS. The inhibitory effect of spinal cord extract for growing neurites was decreased in the KO mice. Two weeks following adult dorsal hemisection of the thoracic spinal cord, Nogo-A KO mice displayed more corticospinal tract (CST) fibers growing toward and into the lesion compared to their wild-type littermates. CST fibers caudal to the lesion-regenerating and/or sprouting from spared intact fibers-were also found to be more frequent in Nogo-A-deficient animals.

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

“…A blow was dealt to this satisfying redundancy model when the Nogo isoforms were knocked out in different combinations [46][47][48] . When expression of Nogo-A and Nogo-B was lost, Strittmatter and colleagues observed limited regeneration in around half of the resulting animals 46 (TABLE 1).…”

Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve

“…12 In the Cnp-Cre þ / À xRtn4 flox/flox hippocampus, we observed B30% decrease in Nogo-A (Figure 1e). The level of the Nogo-A splice variant Nogo-B was elevated in the optic nerve, spinal cord, cortex and hippocampus, suggesting a compensatory upregulation of this protein in oligodendrocytes 7 (Figures 1b-e). By immunohistochemistry in the optic nerve ( Figure 1f) and corpus callosum (Figure 1g), adenomatous polyposis coli (APC)-positive oligodendrocytes were found to contain Nogo-A in control Cnp-Cre þ / À animals, but lacked Nogo-A in Cnp-Cre þ / À xRtn4 flox/flox mice.…”

“…2 Neutralizing Nogo-A by functionblocking antibodies or genetic knockout (KO) has been shown to improve axonal sprouting and regeneration in the injured spinal cord and brain. [6][7][8][9][10][11] In addition to oligodendrocytes and myelin, Nogo-A is expressed in growing and immature neurons, as well as in some adult neurons. 12,13 Neurons express Nogo-A receptors such as the Nogo-66 receptor 1 (NgR1) 14 and the Nogo-A-D20-specific sphingosine 1-phosphate receptor 2 (S1PR2).…”

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

“…41 Recent characterization of plasticity following SCI in three lines of mice lacking one or more Nogo molecules has been similarly perplexing. While corticospinal axon sprouting following spinal hemisection was evident and apparently robust in some mice, 42,43 almost no augmentation of regeneration or sprouting was seen in others. 44 Immunizing mice with MAG-plusNogoA enhances regeneration and/or sprouting of corticospinal axons following spinal hemisection; however, myelin immunization has a greater overall effect than MAG/NogoA immunization.…”