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The Journal of Neuroscience, January 3, 2007, 27(1):220-225; doi:10.1523/JNEUROSCI.4175-06.2007

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Brief Communications
NGF Regulates the Expression of Axonal LINGO-1 to Inhibit Oligodendrocyte Differentiation and Myelination

Xinhua Lee,¹ Zhongshu Yang,¹ Zhaohui Shao,¹ Sheila S. Rosenberg,² Melissa Levesque,¹ R. Blake Pepinsky,¹ Mengsheng Qiu,³ Robert H. Miller,⁴ Jonah R. Chan,² and Sha Mi¹

¹Department of Discovery Biology, Biogen Idec, Cambridge, Massachusetts 02142, ²Department of Cell and Neurobiology, Zilkha Neurogenetic Institute, University of Southern California, Keck School of Medicine, Los Angeles, California 90033, ³Department of Anatomy and Neurobiology, University of Louisville, Louisville, Kentucky 40202, and ⁴Department of Neurosciences, Case School of Medicine, Cleveland, Ohio 44106

Correspondence should be addressed to either of the following: Dr. Jonah R. Chan, Zilkha Neurogenetic Institute, Keck School of Medicine at University of Southern California, Department of Cell and Neurobiology, 1501 San Pablo Street ZNI 421, Los Angeles, CA 90033, Email: jonah.chan{at}usc.edu; or Dr. Sha Mi, Biogen Idec, Discovery Biology, 14 Cambridge Center, Cambridge, MA 02142, Email: sha.mi{at}biogenidec.com

Neurons and glia share a mutual dependence in establishing a functional relationship, and none is more evident than the process by which axons control myelination. Here, we identify LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) as a potent axonal inhibitor of oligodendrocyte differentiation and myelination that is regulated by nerve growth factor and its cognate receptor TrkA in a dose-dependent manner. Whereas LINGO-1 expressed by oligodendrocyte progenitor cells was previously identified as an inhibitor of differentiation, we demonstrate that axonal expression of LINGO-1 inhibits differentiation with equal potency. Disruption of LINGO-1 on either cell type is sufficient to overcome the inhibitory action and promote differentiation and myelination, independent of axon diameter. Furthermore, these results were recapitulated in transgenic mice overexpressing the full length LINGO-1 under the neuronal promoter synapsin. Myelination was greatly inhibited in the presence of enforced axonal LINGO-1. The implications of these results relate specifically to the development of potential therapeutics targeting extrinsic growth factors that may regulate the axonal expression of modulators of oligodendrocyte development.

Key words: oligodendrocyte; myelination; LINGO-1; neurotrophin; differentation; dorsal root ganglion

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Received Sept. 22, 2006; revised Nov. 27, 2006; accepted Nov. 29, 2006.

Correspondence should be addressed to either of the following: Dr. Jonah R. Chan, Zilkha Neurogenetic Institute, Keck School of Medicine at University of Southern California, Department of Cell and Neurobiology, 1501 San Pablo Street ZNI 421, Los Angeles, CA 90033, Email: jonah.chan{at}usc.edu; or Dr. Sha Mi, Biogen Idec, Discovery Biology, 14 Cambridge Center, Cambridge, MA 02142, Email: sha.mi{at}biogenidec.com

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