Pten Deletion in Adult Hippocampal Neural Stem/Progenitor Cells Causes Cellular Abnormalities and Alters Neurogenesis
Pten Deletion in Adult Hippocampal Neural Stem/Progenitor Cells Causes Cellular Abnormalities and Alters Neurogenesis
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DOI：
10.1523/jneurosci.5462-11.2012
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发表时间：
2012-04-25
影响因子：
5.3
通讯作者：
Parada, Luis F.
中科院分区：
文献类型：
--
作者：
Amiri, Anahita;Cho, Woosung;Parada, Luis F.
成年神经发生在哺乳动物的有限大脑区域中持续存在，并受到各种生理和病理条件的影响。肿瘤抑制基因 Pten 参与成人神经发生，并在患有大头畸形的自闭症患者亚群中发生突变；然而，之前尚未研究过 PTEN 在成人神经发生中的作用与自闭症病因之间的联系。此外，海马体（成人神经发生的大脑区域之一）在自闭症发展中的作用尚不清楚。在这里，我们发现，消除海马齿状回颗粒下区成体神经干细胞中的 Pten 会导致干细胞/祖细胞的增殖率更高并加速分化，从而导致神经干细胞库的耗尽并增加后期向星形胶质细胞谱系的分化。 Pten 缺失的干/祖细胞发育成极性异常的肥大神经元。此外，Pten 突变小鼠患有大头畸形，并表现出社交互动和癫痫活动障碍。我们的数据揭示了 PTEN 在成人海马神经发生中的新功能，并表明其在异常社会行为的发病机制中的作用。
Adult neurogenesis persists throughout life in restricted brain regions in mammals and is affected by various physiological and pathological conditions. The tumor suppressor gene Pten is involved in adult neurogenesis and is mutated in a subset of autism patients with macrocephaly; however, the link between the role of PTEN in adult neurogenesis and the etiology of autism has not been studied before. Moreover, the role of hippocampus, one of the brain regions where adult neurogenesis occurs, in development of autism is not clear. Here, we show that ablating Pten in adult neural stem cells in the subgranular zone of hippocampal dentate gyrus results in higher proliferation rate and accelerated differentiation of the stem/progenitor cells, leading to depletion of the neural stem cell pool and increased differentiation toward the astrocytic lineage at later stages. Pten-deleted stem/progenitor cells develop into hypertrophied neurons with abnormal polarity. Additionally, Pten mutant mice have macrocephaly and exhibit impairment in social interactions and seizure activity. Our data reveal a novel function for PTEN in adult hippocampal neurogenesis and indicate a role in the pathogenesis of abnormal social behaviors.