Kozareva Danka A, Moloney Gerard M, Hoban Alan E, Rossini Valerio, Nally Ken, Cryan John F, Nolan Yvonne M
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
APC Microbiome Ireland, University College Cork, Cork, Ireland.
Neuronal Signal. 2019 Mar;3(1):NS20180177. doi: 10.1042/NS20180177. Epub 2019 Feb 22.
Microglia are an essential component of the neurogenic niche in the adult hippocampus and are involved in the control of neural precursor cell (NPC) proliferation, differentiation and the survival and integration of newborn neurons in hippocampal circuitry. Microglial and neuronal cross-talk is mediated in part by the chemokine fractalkine/chemokine (C-X3-C motif) ligand 1 (CX3CL1) released from neurons, and its receptor CX3C chemokine receptor 1 (CX3CR1) which is expressed on microglia. A disruption in this pathway has been associated with impaired neurogenesis yet the specific molecular mechanisms by which this interaction occurs remain unclear. The orphan nuclear receptor TLX (Nr2e1; homologue of the Drosophila tailless gene) is a key regulator of hippocampal neurogenesis, and we have shown that in its absence microglia exhibit a pro-inflammatory activation phenotype. However, it is unclear whether a disturbance in CX3CL1/CX3CR1 communication mediates an impairment in TLX-related pathways which may have subsequent effects on neurogenesis. To this end, we assessed miRNA expression of up- and down-stream signalling molecules of TLX in the hippocampus of mice lacking CX3CR1. Our results demonstrate that a lack of CX3CR1 is associated with altered expression of TLX and its downstream targets in the hippocampus without significantly affecting upstream regulators of TLX. Thus, TLX may be a potential participant in neural stem cell (NSC)-microglial cross-talk and may be an important target in understanding inflammatory-associated impairments in neurogenesis.
小胶质细胞是成年海马体神经源性微环境的重要组成部分，参与神经前体细胞（NPC）增殖、分化的调控，以及新生神经元在海马体神经回路中的存活和整合。小胶质细胞与神经元之间的相互作用部分是由神经元释放的趋化因子fractalkine/趋化因子（C-X3-C基序）配体1（CX3CL1）及其在小胶质细胞上表达的受体CX3C趋化因子受体1（CX3CR1）介导的。该信号通路的破坏与神经发生受损有关，但这种相互作用发生的具体分子机制仍不清楚。孤儿核受体TLX（Nr2e1；果蝇无尾基因的同源物）是海马体神经发生的关键调节因子，我们已经表明，在缺乏TLX的情况下，小胶质细胞表现出促炎激活表型。然而，尚不清楚CX3CL1/CX3CR1信号传导的紊乱是否介导了TLX相关信号通路的损伤，而这可能随后对神经发生产生影响。为此，我们评估了缺乏CX3CR1的小鼠海马体中TLX上下游信号分子的miRNA表达。我们的结果表明，缺乏CX3CR1与海马体中TLX及其下游靶点的表达改变有关，而对TLX的上游调节因子没有显著影响。因此，TLX可能是神经干细胞（NSC）-小胶质细胞相互作用的潜在参与者，可能是理解神经发生中炎症相关损伤的重要靶点。
