Center of Stem Cell and Regenerative Medicine and Department of Neurology of the Second Affiliated Hospital, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Department of Neurology of the First Affiliated Hospital, Interdisciplinary Institute of Neuroscience and Technology, Zhejiang University School of Medicine, Hangzhou 310029, China.
Stem Cell Reports. 2022 Jul 12;17(7):1666-1682. doi: 10.1016/j.stemcr.2022.05.016. Epub 2022 Jun 23.
Hippocampal neurogenesis declines with aging. Wnt ligands and antagonists within the hippocampal neurogenic niche regulate the proliferation of neural progenitor cells and the development of new neurons, and the changes of their levels in the niche mediate aging-associated decline of neurogenesis. We found that RNA-binding protein LIN28A remained existent in neural progenitor cells and granule neurons in the adult hippocampus and that it decreased with aging. Lin28a knockout inhibited the responsiveness of neural progenitor cells to niche Wnt agonists and reduced neurogenesis, thus impairing pattern separation. Overexpression of Lin28a increased the proliferation of neural progenitor cells, promoted the functional integration of newborn neurons, restored neurogenesis in Wnt-deficient dentate gyrus, and rescued the impaired pattern separation in aging mice. Our data suggest that LIN28A regulates adult hippocampal neurogenesis as an intracellular mechanism by responding to niche Wnt signals, and its decrease is involved in aging-associated decline of hippocampal neurogenesis and related cognitive functions.
海马体神经发生随着年龄的增长而衰退。海马体神经发生龛内的 Wnt 配体和拮抗剂调节神经祖细胞的增殖和新神经元的发育，其水平的变化介导了与衰老相关的神经发生衰退。我们发现 RNA 结合蛋白 LIN28A 存在于成年海马体的神经祖细胞和颗粒神经元中，并随着年龄的增长而减少。Lin28a 敲除抑制了神经祖细胞对龛 Wnt 激动剂的反应性，并减少了神经发生，从而损害了模式分离。Lin28a 的过表达增加了神经祖细胞的增殖，促进了新生神经元的功能整合，恢复了 Wnt 缺陷齿状回中的神经发生，并挽救了衰老小鼠中受损的模式分离。我们的数据表明，LIN28A 作为一种细胞内机制，通过响应龛 Wnt 信号来调节成年海马体神经发生，其减少参与了与衰老相关的海马体神经发生和相关认知功能的衰退。
