Cdk5 regulates accurate maturation of newborn granule cells in the adult hippocampus.
Cdk5 regulates accurate maturation of newborn granule cells in the adult hippocampus.
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DOI：
10.1371/journal.pbio.0060272
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发表时间：
2008-11-11
期刊：
影响因子：
9.8
通讯作者：
Gage FH
中科院分区：
文献类型：
--
作者：
Jessberger S;Aigner S;Clemenson GD Jr;Toni N;Lie DC;Karalay O;Overall R;Kempermann G;Gage FH
新生的颗粒细胞经过形态学和电生理学的成熟过程，在功能上整合到成年齿状回的突触回路中。未成熟神经元和从它们延伸的神经突找到它们的适当位置和靶区域的分子机制在很大程度上仍然未知。在这里，我们表明，使用逆转录病毒为基础的策略，在新生细胞中的细胞周期蛋白依赖性激酶5（cdk5）活性的单细胞特异性敲低导致树突状细胞的异常生长，这与新生细胞迁移模式的改变有关。尽管cdk5缺陷细胞中棘的形成和成熟减少，但异常树突在门神经元上形成异位突触。这些观察确定cdk5是至关重要的参与成熟和树突延伸的新生神经元在成人神经发生的过程中。这里提供的数据也表明了精确的树突靶向和随后的突触形成之间的机械分离。神经干细胞在哺乳动物海马体中分裂并产生新的神经元。经过一个独特的成熟过程，新生神经元在功能上整合到预先存在的电路中，并似乎参与海马功能，这与某些形式的学习和记忆密切相关。然而，新神经元找到它们的位置并投射到它们适当的靶区域的分子机制在很大程度上仍然未知。我们在这里表明，细胞类型特异性减少细胞周期蛋白依赖性激酶5（cdk5）活性在新生神经元的结果受损的神经元迁移，并导致不正确的靶向神经元过程的扩展。引人注目的是，从新生细胞延伸的异位过程突触整合，这表明从新生神经元延伸的过程的准确靶向与随后的突触形成之间的分离，这可能对神经干细胞在神经系统疾病中的恢复性使用具有重要意义。新的神经元在海马体中一生都在诞生。新生神经元中细胞类型特异性单基因消融揭示了激酶cdk5调节神经元过程的生长，确定了成人大脑中神经元整合的关键机制。
Newborn granule cells become functionally integrated into the synaptic circuitry of the adult dentate gyrus after a morphological and electrophysiological maturation process. The molecular mechanisms by which immature neurons and the neurites extending from them find their appropriate position and target area remain largely unknown. Here we show that single-cell–specific knockdown of cyclin-dependent kinase 5 (cdk5) activity in newborn cells using a retrovirus-based strategy leads to aberrant growth of dendritic processes, which is associated with an altered migration pattern of newborn cells. Even though spine formation and maturation are reduced in cdk5-deficient cells, aberrant dendrites form ectopic synapses onto hilar neurons. These observations identify cdk5 to be critically involved in the maturation and dendrite extension of newborn neurons in the course of adult neurogenesis. The data presented here also suggest a mechanistic dissociation between accurate dendritic targeting and subsequent synapse formation. Neural stem cells divide and generate new neurons throughout life in the mammalian hippocampus. After a distinct maturation process, newborn neurons become functionally integrated into the preexisting circuitry and appear to participate in hippocampal function, which is critically involved in certain forms of learning and memory. However, the molecular mechanisms by which new neurons find their position and project to their appropriate target area remain largely unknown. We here show that cell-type–specific reduction of cyclin-dependent kinase 5 (cdk5) activity in newborn neurons results in impaired neuronal migration and leads to the extension of incorrectly targeted neuronal processes. Strikingly, ectopic processes extending from newborn cells synaptically integrate, suggesting a dissociation between accurate targeting of processes extending from newborn neurons and subsequent synapse formation, which might have important implications for the restorative use of neural stem cells in neurological disease. New neurons are born throughout life in the hippocampus. Cell-type-specific, single-gene ablation in newborn neurons reveals that the kinase cdk5 regulates growth of neuronal processes, identifying a key mechanism of neuronal integration within the adult brain.
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影响因子：
2.5
作者：
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通讯作者：
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