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.

Download full-text


Available from: Justin D Lathia
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurogenesis, the process of generating new neurons in the brain, fascinates researchers for its promise to affect multiple cognitive and functional processes in both health and disease. Many cellular pathways are involved in the regulation of neurogenesis, a complexity exemplified by the extensive regulation of this process during brain development. Toll-like receptors (TLRs), hallmarks of innate immunity, are increasingly implemented in various central nervous system plasticity-related processes including neurogenesis. As TLRs are involved in neurodegenerative disorders, understanding the involvement of TLRs in neurogenesis may hold keys for future therapeutic interventions. Herein, we describe the current knowledge on the involvement of TLRs in neurogenesis and neuronal plasticity and point to current knowledge gaps in the field.
    Full-text · Article · Aug 2014 · Frontiers in Neuroscience
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Toll-like receptors (TLRs) are transmembrane pattern-recognition receptors that initiate signals in response to diverse pathogen-associated molecular patterns. Several groups have recently reported a role for TLR2 and TLR4 in ischemic stroke-induced brain injury. However, relatively little is known about the role of TLR8 in ischemic stroke. Here we provide the first evidence that TLR8 activation plays a detrimental role in stroke outcome by promoting neuronal apoptosis and T cell-mediated post-stroke inflammation. TLR8 is expressed in cerebral cortical neurons, where its levels and downstream signaling via JNK are increased in response to oxygen glucose deprivation (OGD). Treatment with a TLR8 agonist activated pro-apoptotic JNK and increased neuronal cell death during OGD. Furthermore, selective knockdown of TLR8 using siRNA protected SH-SY5Y cells following OGD, and TLR8 agonist administration in vivo increased mortality, neurological deficit and T cell infiltration following stroke. Taken together, our findings indicate a detrimental role for neuronal TLR8 signaling in the triggering of post-stroke inflammation and neuronal death.
    Full-text · Article · Oct 2013 · Experimental Neurology
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In the process of neurogenesis, neural progenitor cells (NPCs) cease dividing and differentiate into postmitotic neurons that grow dendrites and an axon, become excitable, and establish synapses with other neurons. Mitochondrial biogenesis and aerobic metabolism provide energy substrates required to support the differentiation, growth and synaptic activity of neurons. Mitochondria may also serve signaling functions and, in this regard, it was recently reported that mitochondria can generate rapid bursts of superoxide (superoxide flashes), the frequency of which changes in response to environmental conditions and signals including oxygen levels and Ca(2+) fluxes. Here we show that the frequency of mitochondrial superoxide flashes increases as embryonic cerebral cortical neurons differentiate from NPCs, and provide evidence that the superoxide flashes serve a signaling function that is critical for the differentiation process. The superoxide flashes are mediated by mitochondrial permeability transition pore (mPTP) opening, and pharmacological inhibition of the mPTP suppresses neuronal differentiation. Moreover, superoxide flashes and neuronal differentiation are inhibited by scavenging of mitochondrial superoxide. Conversely, manipulations that increase superoxide flash frequency accelerate neuronal differentiation. Our findings reveal a regulatory role for mitochondrial superoxide flashes, mediated by mPTP opening, in neuronal differentiation.
    Full-text · Article · Oct 2013 · PLoS ONE
Show more