Ciliary neurotrophic factor receptor regulation of adult forebrain neurogenesis.
Ciliary neurotrophic factor receptor regulation of adult forebrain neurogenesis.
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DOI：
10.1523/jneurosci.3386-12.2013
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发表时间：
2013-01-16
期刊：
影响因子：
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通讯作者：
MacLennan AJ
中科院分区：
文献类型：
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作者：
Lee N;Batt MK;Cronier BA;Jackson MC;Bruno Garza JL;Trinh DS;Mason CO;Spearry RP;Bhattacharya S;Robitz R;Nakafuku M;MacLennan AJ
内源性神经干/祖细胞（NSP）的适当靶向操作可能有助于创伤、中风和神经退行性疾病的治疗。这种疗法的先决条件是更好地理解体内调节成体NSP细胞的机制。间接数据表明，内源性睫状神经营养因子（CNTF）受体信号可能抑制NSP细胞的神经元分化。我们挑战脑室下区（SVZ）细胞在体内与低浓度的CNTF的解剖特征细胞含有功能性CNTF受体。我们发现B型“干”细胞高度反应，而C型“传递放大”细胞和A型成神经细胞明显无反应，SVZ外发现的GFAP+星形胶质细胞也是如此。CNTF在急性BrdU给药标记的B型细胞亚群中被鉴定。用“floxed”CNTF受体α（CNTFRα）小鼠系和驱动NSP细胞中Cre重组酶（Cre）表达的基因构建体破坏SVZ NSP细胞中的体内CNTF受体信号传导，导致SVZ相关成神经细胞和新嗅球神经元的增加，以及嗅球神经元群体中神经元亚型特异性的成人发病增加。用重组腺相关病毒（AAV-Cre）破坏SVZ NSP细胞中的成人发病受体也导致神经发生增加。然而，B型细胞群的维持显然不受受体破坏的影响。总之，数据表明，B型干细胞中的内源性CNTF受体信号传导抑制成人神经发生，并进一步表明这种调节可能以神经元亚型特异性方式发生。
Appropriately targeted manipulation of endogenous neural stem progenitor (NSP) cells may contribute to therapies for trauma, stroke, and neurodegenerative disease. A prerequisite to such therapies is a better understanding of the mechanisms regulating adult NSP cells in vivo. Indirect data suggest that endogenous ciliary neurotrophic factor (CNTF) receptor signaling may inhibit neuronal differentiation of NSP cells. We challenged subventricular zone (SVZ) cells in vivo with low concentrations of CNTF to anatomically characterize cells containing functional CNTF receptors. We found that type B “stem” cells are highly responsive while type C “transit-amplifying” cells and type A neuroblasts are remarkably unresponsive, as are GFAP+ astrocytes found outside the SVZ. CNTF was identified in a subset of type B cells that label with acute BrdU administration. Disruption of in vivo CNTF receptor signaling in SVZ NSP cells, with a “floxed” CNTF receptor α (CNTFRα) mouse line and a gene construct driving Cre recombinase (Cre) expression in NSP cells, led to increases in SVZ-associated neuroblasts and new olfactory bulb neurons, as well as a neuron subtype specific, adult-onset increase in olfactory bulb neuron populations. Adult onset receptor disruption in SVZ NSP cells with a recombinant adeno-associated virus (AAV-Cre) also led to increased neurogenesis. However, the maintenance of type B cell populations was apparently unaffected by the receptor disruption. Together, the data suggest that endogenous CNTF receptor signaling in type B stem cells inhibits adult neurogenesis, and further suggest that the regulation may occur in a neuron subtype specific manner.