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The Journal of Neuroscience, December 17, 2008, 28(51):13978-13984; doi:10.1523/JNEUROSCI.2140-08.2008

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Brief Communications
Toll-Like Receptor 3 Is a Negative Regulator of Embryonic Neural Progenitor Cell Proliferation

Justin D. Lathia,^1,2 * Eitan Okun,^1 * Sung-Chun Tang,^1,3 * Kathleen Griffioen,¹ Aiwu Cheng,¹ Mohamed R. Mughal,¹ Gloria Laryea,¹ Pradeep K. Selvaraj,⁴ Charles ffrench-Constant,^2,5 Tim Magnus,^1,6 Thiruma V. Arumugam,^1,4 and Mark P. Mattson^1,7

¹Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224, ²Centre for Brain Repair and Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom, ³Department of Neurology, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin 640, Taiwan, ⁴Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, ⁵Medical Research Council Centre for Regenerative Medicine and Multiple Sclerosis Society Translational Research Centre, University of Edinburgh, Queens Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom, ⁶Neurologische Universitätsklinik, Universität Hamburg, 20246 Hamburg, Germany, and ⁷Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Correspondence should be addressed to Dr. Mark P. Mattson, Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, MD 21224. Email: mattsonm{at}grc.nia.nih.gov

Toll-like receptors (TLRs) play important roles in innate immunity. Several TLR family members have recently been shown to be expressed by neurons and glial cells in the adult brain, and may mediate responses of these cells to injury and infection. To address the possibility that TLRs play a functional role in development of the nervous system, we analyzed the expression of TLRs during different stages of mouse brain development and assessed the role of TLRs in cell proliferation. TLR3 protein is present in brain cells in early embryonic stages of development, and in cultured neural stem/progenitor cells (NPC). NPC from TLR3-deficient embryos formed greater numbers of neurospheres compared with neurospheres from wild-type embryos. Numbers of proliferating cells, as assessed by phospho histone H3 and proliferating cell nuclear antigen labeling, were also increased in the developing cortex of TLR3-deficient mice compared with wild-type mice in vivo. Treatment of cultured embryonic cortical neurospheres with a TLR3 ligand (polyIC) significantly reduced proliferating (BrdU-labeled) cells and neurosphere formation in wild type but not TLR3^–/–-derived NPCs. Our findings reveal a novel role for TLR3 in the negative regulation of NPC proliferation in the developing brain.

Key words: stem cells; embryo; immunity; cortex; neurogenesis; ventricle

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Received May 9, 2008; revised Sept. 15, 2008; accepted Nov. 4, 2008.

Correspondence should be addressed to Dr. Mark P. Mattson, Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, MD 21224. Email: mattsonm{at}grc.nia.nih.gov

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