CXCR4 prevents dispersion of granule neuron precursors in the adult dentate gyrus
CXCR4 prevents dispersion of granule neuron precursors in the adult dentate gyrus
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DOI：
10.1002/hipo.22180
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发表时间：
2013-12
期刊：
影响因子：
3.5
通讯作者：
Clara Schultheiß;Philipp Abe;Frauke Hoffmann;Wiebke Mueller;Anna-Elisabeth Kreuder;D. Schütz;S. Haege;C. Redecker;Silke Keiner;Suresh Kannan;J. Claasen;F. Pfrieger;R. Stumm
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文献类型：
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作者：
Clara Schultheiß;Philipp Abe;Frauke Hoffmann;Wiebke Mueller;Anna-Elisabeth Kreuder;D. Schütz;S. Haege;C. Redecker;Silke Keiner;Suresh Kannan;J. Claasen;F. Pfrieger;R. Stumm
成体齿状回 (DG) 中的神经发生产生新的颗粒神经元，这些神经元在颗粒细胞层 (GCL) 的内部三分之一处分化。这些神经元的迁移前体来自颗粒下区 (SGZ) 的神经干细胞 (NSC)。尽管已经确定包括癫痫和中风在内的病理状况会导致颗粒神经元前体的分散，但人们对调节其正常位置的因素知之甚少。基于趋化因子CXCL12在成人GCL中的高表达及其在发育过程中指导神经元迁移的作用，我们探讨了CXCL12受体CXCR4在成人神经发生中的功能。使用转基因报告小鼠，我们检测了成年和老年小鼠的 NSC、神经元定向祖细胞以及未成熟神经元中的 Cxcr4-GFP 表达。通过免疫印迹和免疫组织化学对海马 NSC 培养物和海马组织进行分析，为 CXCL12 促进体内和体外 NSC 中 CXCR4 受体的磷酸化/激活提供了证据。使用 Cre 技术删除出生后或成熟 DG 的 NSC 中的 Cxcr4 会减少神经发生。成熟 DG 中的 Cxcr4 消融 50 天后，SGZ 显示 Sox2 阳性神经干/早期祖细胞、NeuroD 阳性神经元定型祖细胞和 DCX 阳性未成熟神经元严重减少。许多未成熟的神经元被异位放置在门和分子内层，并且一些神经元形成异常的树突形态。只有少数错位的细胞作为异位神经元永久存活。因此，CXCR4 信号传导维持 DG 中的 NSC 池，并将 GCL 的内部三分之一指定为未成熟颗粒神经元的分化区域。 © 2013 Wiley 期刊公司。
Neurogenesis in the adult dentate gyrus (DG) generates new granule neurons that differentiate in the inner one‐third of the granule cell layer (GCL). The migrating precursors of these neurons arise from neural stem cells (NSCs) in the subgranular zone (SGZ). Although it is established that pathological conditions, including epilepsy and stroke, cause dispersion of granule neuron precursors, little is known about the factors that regulate their normal placement. Based on the high expression of the chemokine CXCL12 in the adult GCL and its role in guiding neuronal migration in development, we addressed the function of the CXCL12 receptor CXCR4 in adult neurogenesis. Using transgenic reporter mice, we detected Cxcr4‐GFP expression in NSCs, neuronal‐committed progenitors, and immature neurons of adult and aged mice. Analyses of hippocampal NSC cultures and hippocampal tissue by immunoblot and immunohistochemistry provided evidence for CXCL12‐promoted phosphorylation/activation of CXCR4 receptors in NSCs in vivo and in vitro. Cxcr4 deletion in NSCs of the postnatal or mature DG using Cre technology reduced neurogenesis. Fifty days after Cxcr4 ablation in the mature DG, the SGZ showed a severe reduction of Sox2‐positive neural stem/early progenitor cells, NeuroD‐positive neuronal‐committed progenitors, and DCX‐positive immature neurons. Many immature neurons were ectopically placed in the hilus and inner molecular layer, and some developed an aberrant dendritic morphology. Only few misplaced cells survived permanently as ectopic neurons. Thus, CXCR4 signaling maintains the NSC pool in the DG and specifies the inner one‐third of the GCL as differentiation area for immature granule neurons. © 2013 Wiley Periodicals, Inc.