Transient enhancement of proliferation of neural progenitors and impairment of their long-term survival in p25 transgenic mice.
Transient enhancement of proliferation of neural progenitors and impairment of their long-term survival in p25 transgenic mice.
复制标题
p25 转基因小鼠神经祖细胞增殖的短暂增强及其长期存活的损害。
DOI：
10.18632/oncotarget.9834
复制
发表时间：
2016-06-28
期刊：
影响因子：
--
通讯作者：
Mao Y
中科院分区：
文献类型：
--
作者：
Zou D;Zhou Y;Liu L;Dong F;Shu T;Zhou Y;Tsai LH;Mao Y
细胞周期蛋白依赖性激酶5（CDK 5）通过p35调节重要的神经元功能。p35响应神经元活性和神经毒性条件而裂解以释放其亚基p25。尽管p25与多种神经退行性疾病有关，但p25介导神经退行性损伤的机制尚未完全阐明。我们的目的是确定p25介导的神经变性对前脑过表达p25（p25 TG）的诱导型转基因小鼠系神经发生的作用。成年神经元祖细胞（NPC）在体内标记BrdU，这是显着增加的数量在脑室下区，海马和皮质的p25转基因小鼠。一致地，在p25 TG小鼠中观察到比对照组更多的有丝分裂细胞，甚至在皮质和CA 1中，这不是神经源性区域。BrdU阳性细胞GFAP或γ-H2 AX阴性，表明它们不是星形胶质细胞或垂死细胞。p25 TG小鼠海马齿状回和皮层神经球数量明显增多，可分化为星形胶质细胞和神经元。然而，p25 TG降低了增殖的NPC的长期存活率，并严重损害了成体神经发生。使用Transwell共培养系统来评估表达p25的原代神经元对成体NPC的影响。与表达p25的神经元共培养下调Ki 67表达，上调裂解的caspase-3，表明细胞间通讯中的旁分泌信号对NPC存活和增殖至关重要。此外，增加的CDK 5活性损害Wnt活化。这项研究表明，p25的过度激活可能会暂时增强NPC的增殖，但会损害其长期生存。
Cyclin-dependent kinase 5 (CDK5) regulates important neuronal functions via p35. p35 undergoes cleavage in response to neuronal activity and neurotoxic conditions to release its subunit p25. Although p25 has been implicated in various neurodegenerative diseases, the mechanisms by which p25 mediates neurodegenerative impairment have not been fully elucidated. We aimed to determine the role of p25-mediated neurodegeneration on neurogenesis in an inducible transgenic mouse line overexpressing p25 (p25 TG) in the forebrain. Adult neuronal progenitor cells (NPCs) were labeled with BrdU in vivo, which were significantly increased in numbers in the subventricular zone, the hippocampus, and the cortex of p25 TG mice. Consistently, more mitotic cells were observed in p25 TG mice than in controls, even in the cortex and the CA1, which are not neurogenic regions. BrdU-positive cells were negative for GFAP or γ-H2AX, suggesting that they are not astrocytes or dying cells. Neurospheres derived from the dentate gyrus and the cortex were significantly increased in p25 TG mice and can be differentiated into astrocytes and neurons. However, p25 TG decreased the long-term survival of proliferating NPCs and severely impaired adult neurogenesis. A Transwell co-culture system was used to assess the influence of p25-expressing primary neurons on adult NPCs. Co-culture with p25-expressing neurons downregulated Ki67 expression and upregulated cleaved caspase-3, indicating that the paracrine signaling in cell-cell communication is essential for NPC survival and proliferation. Moreover, increased CDK5 activity impairs Wnt activation. This study demonstrates that hyperactivation of p25 may temporarily enhance NPC proliferation, but impair their long-term survival.
登录
查看更多内容
影响因子：
4.3
作者：
Butti E;Cusimano M;Bacigaluppi M;Martino G
通讯作者：
Martino G
影响因子：
7.7
作者：
Chatzi C;Schnell E;Westbrook GL
通讯作者：
Westbrook GL
影响因子：
64.5
作者：
Bonaguidi MA;Wheeler MA;Shapiro JS;Stadel RP;Sun GJ;Ming GL;Song H
通讯作者：
Song H
影响因子：
9.8
作者：
Jessberger S;Aigner S;Clemenson GD Jr;Toni N;Lie DC;Karalay O;Overall R;Kempermann G;Gage FH
通讯作者：
Gage FH
影响因子：
3.3
作者：
Kahn OI;Sharma V;González-Billault C;Baas PW
通讯作者：
Baas PW