Sci. STKE, 6 May 2003
NEUROBIOLOGY Nogo Knockouts
Understanding the molecular basis for inhibition of axon growth of injured adult central nervous system neurons would provide targets for potential therapies to aid in the treatment of cases such as spinal cord injury. Components of oligodendrocyte-generated myelin (central myelin) that inhibit axon outgrowth include Nogo-A, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein. In vivo and in vitro studies that manipulated Nogo-A activity suggested that neutralizing Nogo-A may allow axon growth and functional recovery. Three groups (Simonen et al., Kim et al., and Zheng et al.) generated Nogo-deficient mice to test this hypothesis. Unfortunately, the results are remarkably dissimilar. Three isoforms of Nogo are produced from a single gene: Nogo-A and Nogo-B by alternative splicing to include or exclude exon 3, and Nogo-C by alternative promoter usage to produce a version lacking the first 3 exons. Binding to the Nogo-66 receptor occurs through a C-terminal domain common to all three isoforms. Simonen et al. knocked out Nogo-A selectively and saw an increase in Nogo-B expression. In vitro spinal cord explants from the Nogo-A knockout (KO) mice inhibited granule neuron outgrowth to a lesser extent than did wild-type explants. In vivo spinal cord lesioning experiments showed increased regenerative outgrowth across the lesioned area as compared with that in wild-type spinal cords. Kim et al. created KO mice that lacked both Nogo-A and Nogo-B. As observed with the Nogo-A KO mice, in vitro assays with explants or dissociated neurons treated with Nogo-A/B KO myelin showed increased axon outgrowth compared with that in the presence of wild-type myelin. Nogo-A/B KO mice also exhibited increased regenerative outgrowth and functional recovery (based on open field locomotor activity) after spinal cord lesions compared with that in wild-type mice. Zheng et al. found quite different results with their mice deficient for all three Nogo isoforms and in their mice deficient for Nogo-A and Nogo-B. Although myelin from the Nogo-A/B KO mice permitted more axon outgrowth in vitro than did wild-type myelin, in vivo, neither the Nogo-A/B KO mice nor the Nogo-A/B/C KO mice exhibited enhanced axonal regeneration in response to spinal cord lesioning. The differences in the targeting vectors for creation of the KO mice and differences in the age of the mice may account for the difference in regenerative capacity of the different mutant strains of mice (see Woolf).
M. Simonen, V. Pedersen, O. Weinmann, L. Schnell, A. Buss, B. Ledermann, F. Christ, G. Sansig, H. van der Putten, M. E. Schwab, Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Neuron 38, 201-211 (2003). [Online Journal]
J.-E. Kim, S. Li, T. GrandPré, D. Qiu, S. M. Strittmatter, Axon regeneration in young adult mice lacking Nogo-A/B. Neuron 38, 187-199 (2003). [Online Journal]
B. Zheng, C. Ho, S. Li, H. Keirstead, O. Steward, M. Tessier-Lavigne, Lack of enhanced spinal regeneration in Nogo-deficient mice. Neuron 38, 213-224 (2003). [Online Journal]
C. J. Woolf, No Nogo, Now where to go? Neuron 38, 153-156 (2003). [Online Journal]
Citation: Nogo Knockouts. Sci. STKE 2003, tw178 (2003).
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