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

Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland 21224, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 01/2009; 28(51):13978-84. DOI: 10.1523/JNEUROSCI.2140-08.2008
Source: PubMed


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.

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    • "TLR5 forms asymmetric homodimers (Zhou et al., 2012) and seems to maintain a stable expression level throughout the developmental process (Kaul et al., 2012) (Figure 2). Nucleic acid sensing TLRs also exhibit differential expression pattern during development; TLR3 expression is already in its highest levels in the early period of cortical development when NPC are highly proliferative (Lathia et al., 2008) (Figure 2). Its expression then declines as neurogenesis and gliogenesis ensues and low expression levels are maintained in the adult (Kaul et al., 2012) (Figure 2). "
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    • "Toll-like receptors (TLRs) are transmembrane pattern-recognition receptors (PRRs) that initiate signals in response to diverse pathogenassociated molecular patterns (PAMPs) (Kawai and Akira, 2007). TLRs are expressed in a variety of mammalian immune-related cell types (Okun et al., 2009) as well as non-immune cells (Lathia et al., 2008; Okun et al., 2010). TLRs are also present in the brain where, until recently, their expression was believed to be limited to microglia, astrocytes and oligodendrocytes (Ma et al., 2006; Tang et al., 2007). "
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    • "NPCs isolated from embryonic C57 mouse cerebral cortex were cultured as floating neurospheres as described previously [17]. Briefly, the telencephalon from embryonic day 14.5 mice was dissected in sterile Hanks’ balanced saline solution (HBSS). "
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