CHD7 maintains neural stem cell quiescence and prevents premature stem cell depletion in the adult hippocampus.
CHD7 maintains neural stem cell quiescence and prevents premature stem cell depletion in the adult hippocampus.
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DOI：
10.1002/stem.1822
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发表时间：
2015-01
期刊：
影响因子：
--
通讯作者：
Basson MA
中科院分区：
文献类型：
--
作者：
Jones KM;Sarić N;Russell JP;Andoniadou CL;Scambler PJ;Basson MA
海马中的神经干/祖细胞（NSC）在整个成年期产生新的神经元。NSC维持在可逆静止状态，不能维持静止状态可导致干细胞库的过早耗尽。维持这种静止状态的表观遗传机制尚未确定。使用可诱导敲除小鼠模型，我们表明染色质重塑因子chromodomain-helicase-DNA-binding protein 7（CHD 7）对于维持NSC静止是必不可少的。成年NSC中CHD 7失活导致海马中干细胞静止的丧失，细胞分裂的短暂增加，随后是神经发生的显著下降。这种NSC静止期的丧失与中年小鼠中NSC的过早丧失有关。我们发现，CHD 7抑制细胞周期进程的几个积极的监管机构的转录，并需要在静止的神经干细胞的Notch靶基因Hes 5的充分诱导。这些发现直接将CHD 7与参与NSC静止的途径联系起来，并确定了第一个在NSC静止和维持中发挥作用的染色质重塑因子。由于CHD 7单倍型功能不全与CHARGE综合征中的一系列认知障碍相关，我们的观察结果可能对理解这些缺陷的基础具有意义。干细胞2015;33：196-210
Neural stem/progenitor cells (NSCs) in the hippocampus produce new neurons throughout adult life. NSCs are maintained in a state of reversible quiescence and the failure to maintain the quiescent state can result in the premature depletion of the stem cell pool. The epigenetic mechanisms that maintain this quiescent state have not been identified. Using an inducible knockout mouse model, we show that the chromatin remodeling factor chromodomain–helicase‐DNA‐binding protein 7 (CHD7) is essential for maintaining NSC quiescence. CHD7 inactivation in adult NSCs results in a loss of stem cell quiescence in the hippocampus, a transient increase in cell divisions, followed by a significant decline in neurogenesis. This loss of NSC quiescence is associated with the premature loss of NSCs in middle‐aged mice. We find that CHD7 represses the transcription of several positive regulators of cell cycle progression and is required for full induction of the Notch target gene Hes5 in quiescent NSCs. These findings directly link CHD7 to pathways involved in NSC quiescence and identify the first chromatin‐remodeling factor with a role in NSC quiescence and maintenance. As CHD7 haplo‐insufficiency is associated with a range of cognitive disabilities in CHARGE syndrome, our observations may have implications for understanding the basis of these deficits. Stem Cells 2015;33:196–210
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