NTPDase2 and purinergic signaling control progenitor cell proliferation in neurogenic niches of the adult mouse brain.
NTPDase2 and purinergic signaling control progenitor cell proliferation in neurogenic niches of the adult mouse brain.
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DOI：
10.1002/stem.1846
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发表时间：
2015-01
期刊：
影响因子：
5.2
通讯作者：
Zimmermann, Herbert
中科院分区：
文献类型：
--
作者：
Gampe, Kristine;Stefani, Jennifer;Hammer, Klaus;Brendel, Peter;Poetzsch, Alexandra;Enikolopov, Grigori;Enjyoji, Keiichi;Acker-Palmer, Amparo;Robson, Simon C.;Zimmermann, Herbert
关键词：
成年哺乳动物心室下区（SVZ）和海马齿状回的干细胞连续生成神经细胞。我们之前已经注意到，SVZ和齿状回亚颗粒层（SGL）中的干/祖细胞表达高水平的质膜结合核苷三磷酸二磷酸水解酶2 (NTPDase2)，这是一种水解细胞外核苷二磷酸和三磷酸的外酶。我们推测，NTPDase2的缺失会增加局部细胞外核苷三磷酸浓度，扰乱嘌呤能信号，促进祖细胞增殖和神经发生。利用新生成的小鼠，我们发现在这些祖细胞富集区，NTPDase2是主要的外核苷酸酶。使用brdu标记方案，我们测量了干细胞增殖并确定了细胞后代在基础条件下的长期存活。Entpd2缺失小鼠的大脑显示SVZ和SGL的祖细胞增殖增加。然而，这种情况在后代的长期存活中没有明显的改变。海马干细胞池和中间祖细胞2型池明显扩大。然而，在3型左右的扩增过程中，这些增殖细胞的实质性比例丢失。细胞损失与双皮质素阳性祖细胞群中CREB磷酸化的减少和激活caspase-3水平的标记增加相平行。我们提出ntpdese2具有清除成人大脑神经源性壁龛中有丝分裂细胞外核苷三磷酸的功能，从而作为核苷酸介导的神经祖细胞增殖和扩增的稳态调节剂。
Nerve cells are continuously generated from stem cells in the adult mammalian subventricular zone (SVZ) and hippocampal dentate gyrus. We have previously noted that stem/progenitor cells in the SVZ and the subgranular layer (SGL) of the dentate gyrus express high levels of plasma membrane-bound nucleoside triphosphate diphosphohydrolase 2 (NTPDase2), an ectoenzyme that hydrolyzes extracellular nucleoside di- and triphosphates. We inferred that deletion of NTPDase2 would increase local extracellular nucleoside triphosphate concentrations perturbing purinergic signaling and boosting progenitor cell proliferation and neurogenesis. Using newly generated mice globally null for Entpd2, we demonstrate that NTPDase2 is the major ectonucleotidase in these progenitor cell rich areas. Using BrdU-labeling protocols, we have measured stem cell proliferation and determined long term survival of cell progeny under basal conditions. Brains of Entpd2 null mice revealed increased progenitor cell proliferation in both the SVZ and the SGL. However, this occurred without noteworthy alterations in long-term progeny survival. The hippocampal stem cell pool and the pool of the intermediate progenitor type-2 cells clearly expanded. However, substantive proportions of these proliferating cells were lost during expansion at around type-3 stage. Cell loss was paralleled by decreases in CREB phosphorylation in the doublecortin-positive progenitor cell population and by an increase in labeling for activated caspase-3 levels. We propose that NTPDase2 has functionality in scavenging mitogenic extracellular nucleoside triphosphates in neurogenic niches of the adult brain, thereby acting as a homeostatic regulator of nucleotide-mediated neural progenitor cell proliferation and expansion.
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