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The Journal of Neuroscience, July 4, 2007, 27(27):7117-7124; doi:10.1523/JNEUROSCI.1541-07.2007

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Development/Plasticity/Repair
The Nogo-66 Receptor NgR1 Is Required Only for the Acute Growth Cone-Collapsing But Not the Chronic Growth-Inhibitory Actions of Myelin Inhibitors

Onanong Chivatakarn,^1,2 Shinjiro Kaneko,³ Zhigang He,³ Marc Tessier-Lavigne,⁴ and Roman J. Giger²

¹Interdepartmental Graduate Program in Neuroscience, ²Center for Aging and Developmental Biology, Department of Biomedical Genetics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, ³Division of Neuroscience, Children's Hospital and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, and ⁴Division of Research, Genentech, Inc., South San Francisco, California 94080

Correspondence should be addressed to Dr. Roman J. Giger, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642. Email: roman_giger{at}urmc.rochester.edu

Neuronal Nogo-66 receptor 1 (NgR1) has been proposed to function as an obligatory coreceptor for the myelin-derived ligands Nogo-A, oligodendrocyte myelin glycoprotein (OMgp), and myelin-associated glycoprotein (MAG) to mediate neurite outgrowth inhibition by these ligands. To examine the contribution of neuronal NgR1 to outgrowth inhibition, we used two different strategies, genetic ablation of NgR1 through the germline and transient short hairpin RNA interference (shRNAi)-mediated knock-down. To monitor growth inhibition, two different paradigms were used, chronic presentation of substrate-bound inhibitor to measure neurite extension and acute application of soluble inhibitor to assay growth cone collapse. We find that regardless of the NgR1 genotype, membrane-bound MAG strongly inhibits neurite outgrowth of primary cerebellar, sensory, and cortical neurons. Similarly, substrate-bound OMgp strongly inhibits neurite outgrowth of NgR1 wild-type and mutant sensory neurons. Consistent with these results, shRNAi-mediated knock-down of neuronal NgR1 does not result in a substantial release of L-MAG (large MAG) inhibition. When applied acutely, however, MAG-Fc and OMgp-Fc induce a modest degree of growth cone collapse that is significantly attenuated in NgR1-null neurons compared with wild-type controls. Based on our findings and previous studies with Nogo-66, we propose that neuronal NgR1 has a circumscribed role in regulating cytoskeletal dynamics after acute exposure to soluble MAG, OMgp, or Nogo-66, but is not required for these ligands to mediate their growth-inhibitory properties in chronic outgrowth experiments. Our results thus provide unexpected evidence that the growth cone-collapsing activities and substrate growth-inhibitory activities of inhibitory ligands can be dissociated. We also conclude that chronic axon growth inhibition by myelin is mediated by NgR1-independent mechanisms.

Key words: neurite outgrowth; growth cone collapse; MAG; OMgp; shRNAi; myelin

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Received April 5, 2007; revised May 23, 2007; accepted May 25, 2007.

Correspondence should be addressed to Dr. Roman J. Giger, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642. Email: roman_giger{at}urmc.rochester.edu

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J. Neurosci. 2007 27: 11451-11452. [Full Text]  

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