Petrik David, Latchney Sarah E, Masiulis Irene, Yun Sanghee, Zhang Zilai, Wu Jiang I, Eisch Amelia J
Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Stem Cells. 2015 Dec;33(12):3655-65. doi: 10.1002/stem.2215. Epub 2015 Oct 9.
Insights from embryonic development suggest chromatin remodeling is important in adult neural stem cells (aNSCs) maintenance and self-renewal, but this concept has not been fully explored in the adult brain. To assess the role of chromatin remodeling in adult neurogenesis, we inducibly deleted Brg1--the core subunit of SWI/SNF-like Brg1/Brm-associated factor chromatin remodeling complexes--in nestin-expressing aNSCs and their progeny in vivo and in culture. This resulted in abnormal adult neurogenesis in the hippocampus, which initially reduced hippocampal aNSCs and progenitor maintenance, and later reduced its responsiveness to physiological stimulation. Mechanistically, deletion of Brg1 appeared to impair cell cycle progression, which is partially due to elevated p53 pathway and p21 expression. Knockdown of p53 rescued the neurosphere growth defects caused by Brg1 deletion. Our results show that epigenetic chromatin remodeling (via a Brg1 and p53/p21-dependent process) determines the aNSCs and progenitor maintenance and responsiveness of neurogenesis.
胚胎发育的相关见解表明，染色质重塑在成体神经干细胞（aNSCs）的维持和自我更新中起着重要作用，但这一概念在成体大脑中尚未得到充分探索。为了评估染色质重塑在成体神经发生中的作用，我们在体内和体外对表达巢蛋白的aNSCs及其子代细胞中可诱导性地敲除了Brg1（SWI/SNF样Brg1/Brm相关因子染色质重塑复合体的核心亚基）。这导致海马体中出现异常的成体神经发生，最初减少了海马体aNSCs和祖细胞的维持，随后降低了其对生理刺激的反应能力。从机制上讲，Brg1的缺失似乎会损害细胞周期进程，这部分是由于p53通路和p21表达升高所致。敲低p53可挽救由Brg1缺失引起的神经球生长缺陷。我们的结果表明，表观遗传染色质重塑（通过Brg1以及p53/p21依赖的过程）决定了aNSCs和祖细胞的维持以及神经发生的反应能力。
