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The Journal of Neuroscience, November 21, 2007, 27(47):13033-13041; doi:10.1523/JNEUROSCI.4290-06.2007

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Neurobiology of Disease
Toll-Like Receptor 3 Is a Potent Negative Regulator of Axonal Growth in Mammals

Jill S. Cameron,¹ Lena Alexopoulou,³ Jacob A. Sloane,¹ Allitia B. DiBernardo,¹ Yinghua Ma,¹ Bela Kosaras,¹ Richard Flavell,^3,4 Stephen M. Strittmatter,⁵ Joseph Volpe,² Richard Sidman,¹ and Timothy Vartanian¹

¹Department of Neurology, Beth Israel Deaconess Medical Center, Program in Neuroscience and the Center for Neurodegeneration and Repair, and ²Department of Neurology, Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, ³Section of Immunobiology and ⁴Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, 06520, ⁵Department of Neurology and Section of Neurobiology, Yale University School of Medicine, New Haven, Connecticut, 06510

Correspondence should be addressed to Timothy Vartanian at the above address. Email: tvartani{at}bidmc.harvard.edu

Toll is a cell surface receptor with well described roles in the developmental patterning of invertebrates and innate immunity in adult Drosophila. Mammalian toll-like receptors represent a family of Toll orthologs that function in innate immunity by recognizing molecular motifs unique to pathogens or injured tissue. One member in this family of pattern recognition receptors, toll-like receptor 3 (TLR3), recognizes viral double-stranded RNA and host mRNA. We examined the expression and function of TLRs in the nervous system and found that TLR3 is expressed in the mouse central and peripheral nervous systems and is concentrated in the growth cones of neurons. Activation of TLR3 by the synthetic ligand polyinosine:polycytidylic acid (poly I:C) or by mRNA rapidly causes growth cone collapse and irreversibly inhibits neurite extension independent of nuclear factor B. Mice lacking functional TLR3 were resistant to the neurodegenerative effects of poly I:C. Neonatal mice injected with poly I:C were found to have fewer axons exiting dorsal root ganglia and displayed related sensorimotor deficits. No effect of poly I:C was observed in mice lacking functional TLR3. Together, these findings provide evidence that an innate immune pattern recognition receptor functions autonomously in neurons to regulate axonal growth and advances a novel hypothesis that this class of receptors may contribute to injury and limited CNS regeneration.

Key words: Toll-like receptor-3; axon; polyinosine:polycytidylic acid; poly I:C; RNA; CNS; danger theory

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Received Oct. 2, 2006; revised Sept. 11, 2007; accepted Oct. 10, 2007.

Correspondence should be addressed to Timothy Vartanian at the above address. Email: tvartani{at}bidmc.harvard.edu

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