MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266000, China.
Stem Cell Reports. 2022 Sep 13;17(9):2081-2096. doi: 10.1016/j.stemcr.2022.07.017. Epub 2022 Aug 25.
Cellular quiescence facilitates maintenance of neural stem cells (NSCs) and their subsequent regenerative functions in response to brain injury and aging. However, the specification and maintenance of NSCs in quiescence from embryo to adulthood remain largely unclear. Here, using Set domain-containing protein 4 (SETD4), an epigenetic determinant of cellular quiescence, we mark a small but long-lived NSC population in deep quiescence in the subventricular zone of adult murine brain. Genetic lineage tracing shows that SETD4 cells appear before neuroectoderm formation and contribute to brain development. In the adult, conditional knockout of Setd4 resulted in quiescence exit of NSCs, generating newborn neurons in the olfactory bulb and contributing to damage repair. However, long period deletion of SETD4 lead to exhaustion of NSC reservoir or SETD4 overexpression caused quiescence entry of NSCs, leading to suppressed neurogenesis. This study reveals the existence of long-lived deep quiescent NSCs and their neurogenetic capacities beyond activation.
细胞静止有利于维持神经干细胞 (NSCs)，并使其在脑损伤和衰老时发挥再生功能。然而，胚胎到成年期NSCs 在静止状态下的分化和维持仍很大程度上不清楚。在这里，我们利用 SET 域蛋白 4（SETD4），一种细胞静止的表观遗传决定因素，标记了成年鼠脑室下区深层静止中的一小部分但具有长期寿命的 NSCs 群体。遗传谱系追踪显示，SETD4 细胞出现在神经外胚层形成之前，并有助于大脑发育。在成年期，条件性敲除 Setd4 导致 NSCs 退出静止，在嗅球中产生新生神经元，并有助于损伤修复。然而，SETD4 的长期缺失会耗尽 NSC 储备，或 SETD4 的过表达会导致 NSCs 进入静止，从而抑制神经发生。这项研究揭示了长期存在的深层静止 NSCs 及其超越激活的神经发生能力。
