Unique role for dentate gyrus microglia in neuroblast survival and in VEGF-induced activation
Unique role for dentate gyrus microglia in neuroblast survival and in VEGF-induced activation
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DOI：
10.1002/glia.23505
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发表时间：
2019-04-01
期刊：
影响因子：
6.2
通讯作者：
Licht, Tamar
中科院分区：
文献类型：
--
作者：
Kreisel, Tirzah;Wolf, Brachi;Licht, Tamar
小胶质细胞(MG)的神经发生作用被认为包括在成年海马神经发生中的积极作用，以及它们在修剪多余的树突和清除死亡的神经母细胞方面的既定作用。然而，这种作用的识别和它在神经源性级联反应中的描述还有待确定。使用白喉毒素辅助MG消融术，我们发现DG-神经干细胞(NSCs)所在位置的MG减少足以阻碍整个海马神经发生，因为新形成的神经母细胞的存活率降低。为了检验位于海马神经原区的MG是否与位于海马区其他部位的MG有本质的不同，我们比较了DG MG和CA1 MG的生长因子反应性。值得注意的是，转基因诱导的强大的神经源性因子血管内皮生长因子仅在DG中诱导了强劲的原位MG扩张和激活，尽管在CA1和其他地方引发了类似的血管生成反应。在时间上，DG特异性MG扩张先于血管生成和神经源性反应。值得注意的是，在血管内皮生长因子诱导的神经发生过程中，即使部分MG减少，也会导致新形成的神经母细胞数量减少到基础水平。对从幼稚的DG和CA1中提取的MG进行转录分析，发现了一组在DG MG中优先表达的基因。值得注意的是，酪氨酸激酶Axl仅在NAIVE和血管内皮生长因子诱导的DG MG中表达，其抑制阻止了血管内皮生长因子对神经再生的增强。综上所述，这些发现揭示了DG MG支持基础和血管内皮生长因子诱导的成年海马神经发生的固有独特特性。
Neurogenic roles of microglia (MG) are thought to include an active role in adult hippocampal neurogenesis in addition to their established roles in pruning surplus dendrites and clearing dead neuroblasts. However, identification of such a role and its delineation in the neurogenic cascade is yet to be established. Using diphtheria toxin-aided MG ablation, we show that MG reduction in the DG-the site where neuronal stem cells (NSCs) reside-is sufficient to impede overall hippocampal neurogenesis due to reduced survival of newly formed neuroblasts. To examine whether MG residing in the hippocampal neurogenic zone are inherently different from MG residing elsewhere in the hippocampus, we compared growth factor responsiveness of DG MG with that of CA1 MG. Strikingly, transgenic induction of the potent neurogenic factor VEGF elicited robust on-site MG expansion and activation exclusively in the DG and despite eliciting a comparable angiogenic response in the CA1 and elsewhere. Temporally, DG-specific MG expansion preceded both angiogenic and neurogenic responses. Remarkably, even partial MG reduction during the process of VEGF-induced neurogenesis led to reducing the number of newly formed neuroblasts to the basal level. Transcriptomic analysis of MG retrieved from the naive DG and CA1 uncovered a set of genes preferentially expressed in DG MG. Notably the tyrosine kinase Axl is exclusively expressed in naive and VEGF-induced DG MG and its inhibition prevented neurogenesis augmentation by VEGF. Taken together, findings uncover inherent unique properties of DG MG of supporting both basal- and VEGF-induced adult hippocampal neurogenesis.