Functional rejuvenation of aged neural stem cells by Plagl2 and anti-Dyrk1a activity.
Functional rejuvenation of aged neural stem cells by Plagl2 and anti-Dyrk1a activity.
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DOI：
10.1101/gad.349000.121
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发表时间：
2022-01-01
影响因子：
10.5
通讯作者：
Kageyama R
中科院分区：
文献类型：
--
作者：
Kaise T;Fukui M;Sueda R;Piao W;Yamada M;Kobayashi T;Imayoshi I;Kageyama R
在这里，Kaise等人从胚胎和成年NSC及其调节剂之间差异表达的核因子中寻找可以使老年小鼠脑中的NSC再生的基因组合。他们发现，诱导锌指转录因子基因Plagl 2和抑制与唐氏综合症相关的基因Dyrk 1a的组合可以使衰老的海马神经干细胞恢复活力，他们得出的结论是，可以逆转神经干细胞的衰老，以连续诱导功能性神经发生。神经干细胞（NSC）的再生潜力在衰老过程中下降，导致认知功能障碍。这种下降涉及衰老相关基因的上调，但这些基因的失活未能逆转海马神经干细胞的衰老。由于许多基因在衰老过程中上调或下调，因此操纵单个基因不足以逆转衰老。在这里，我们寻找一种基因组合，可以从胚胎和成人神经干细胞及其调节剂之间的差异表达的核因子，在老年小鼠脑神经干细胞的年轻化。我们发现，诱导锌指转录因子基因Plagl2和抑制Dyrk1a（一种与唐氏综合征（一种已知加速衰老的遗传疾病）相关的基因）的组合，使已经失去增殖和神经原性潜力的老年海马神经干细胞恢复活力。这种再生的神经干细胞增殖，并在幼年海马中观察到的水平上连续产生新的神经元，从而改善认知能力。表观基因组、转录组和实时成像分析表明，这种基因组合通过改变其染色质可及性诱导胚胎相关基因的上调和年龄相关基因的下调，从而使老化休眠的NSC恢复活力，使其像幼年活跃的NSC一样发挥作用。因此，神经干细胞的老化可以被逆转，以持续诱导功能性神经发生，为治疗与年龄相关的神经系统疾病提供了一种方法。
Here, Kaise et al. searched for a gene combination that can rejuvenate NSCs in the aged mouse brain from nuclear factors differentially expressed between embryonic and adult NSCs and their modulators. They found that a combination of inducing the zinc finger transcription factor gene Plagl2 and inhibiting Dyrk1a, a gene associated with Down syndrome, rejuvenated aged hippocampal NSCs, and they conclude that aging of NSCs can be reversed to induce functional neurogenesis continuously. The regenerative potential of neural stem cells (NSCs) declines during aging, leading to cognitive dysfunctions. This decline involves up-regulation of senescence-associated genes, but inactivation of such genes failed to reverse aging of hippocampal NSCs. Because many genes are up-regulated or down-regulated during aging, manipulation of single genes would be insufficient to reverse aging. Here we searched for a gene combination that can rejuvenate NSCs in the aged mouse brain from nuclear factors differentially expressed between embryonic and adult NSCs and their modulators. We found that a combination of inducing the zinc finger transcription factor gene Plagl2 and inhibiting Dyrk1a, a gene associated with Down syndrome (a genetic disorder known to accelerate aging), rejuvenated aged hippocampal NSCs, which already lost proliferative and neurogenic potential. Such rejuvenated NSCs proliferated and produced new neurons continuously at the level observed in juvenile hippocampi, leading to improved cognition. Epigenome, transcriptome, and live-imaging analyses indicated that this gene combination induces up-regulation of embryo-associated genes and down-regulation of age-associated genes by changing their chromatin accessibility, thereby rejuvenating aged dormant NSCs to function like juvenile active NSCs. Thus, aging of NSCs can be reversed to induce functional neurogenesis continuously, offering a way to treat age-related neurological disorders.
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影响因子：
64.5
作者：
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通讯作者：
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作者：
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通讯作者：
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