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The Journal of Neuroscience, December 1, 2002, 22(23):10368-10376
Nogo-A and Myelin-Associated Glycoprotein Mediate Neurite Growth Inhibition by Antagonistic Regulation of RhoA and Rac1
Barbara Niederöst1, Thomas Oertle2, Jens Fritsche2, R. Anne McKinney2, and Christine E. Bandtlow1 1 Institute of Medical Chemistry and Biochemistry, Leopold-Franzens-University of Innsbruck, A-6020 Innsbruck, Austria, and 2 Brain Research Institute, University of Zurich and Swiss Federal Institute of Technology of Zurich, CH-8057 Zurich, Switzerland
The adult mammalian CNS has a limited capacity for nerve regeneration and structural plasticity. The presence of glia-derived inhibitory factors myelin-associated glycoprotein (MAG) and Nogo-A have been suggested to provide a nonpermissive environment for elongating nerve fibers. In particular, Nogo-A, an integral membrane protein predominantly expressed by oligodendrocytes, has been demonstrated to impair neurite growth in vitro and in vivo. Structure function analysis revealed that Nogo-A protein contains at least two active domains, NiG and Nogo-66, with diverse effects on neurite outgrowth and cell spreading. We now provide evidence that these inhibitory domains mediate their effects via an antagonistic regulation of the small GTPases RhoA and Rac1, resulting in activation of RhoA and suppression of Rac1. By inactivating RhoA with C3 transferase or the downstream effector Rho-kinase ROCK with Y27632, the inhibitory effects of both Nogo-A fragments and MAG on neurite outgrowth and oligodendrocyte-mediated growth cone collapse were abolished. Furthermore, we show that the recently cloned receptor for Nogo-66 and MAG, NgR, is not necessary for either NiG- or MAG-induced RhoA activation.
Key words: regeneration; neurite growth inhibitors; CNS myelin; Nogo-A; MAG; small GTPases; signal transduction
Copyright © 2002 Society for Neuroscience 0270-6474/02/222310368-09$05.00/0
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