Histone H2AX-dependent GABAA receptor regulation of stem cell proliferation
Histone H2AX-dependent GABAA receptor regulation of stem cell proliferation
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DOI：
10.1038/nature06488
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发表时间：
2008-01-24
期刊：
影响因子：
64.8
通讯作者：
Ernfors, Patrik
中科院分区：
文献类型：
--
作者：
Andang, Michael;Hjerling-Leffler, Jens;Ernfors, Patrik
干细胞自我更新意味着在多能性的持续维持下增殖。干细胞数量的微小变化可能导致分化细胞数量的巨大差异，从而导致显著的生理后果。增殖通常在G1期调节，这与分化和细胞周期停滞有关（1）。然而，胚胎干细胞（ES）可能缺乏G1检查点（2，3）。已知“DNA损伤”S/G2细胞周期检查点途径中的增殖调节在维持染色质结构完整性中的作用（4）。在这里，我们表明，通过GABA（A）受体的自分泌/旁分泌γ-氨基丁酸（GABA）信号传导负控制ES细胞和外周神经嵴干（NCS）细胞增殖、植入前胚胎生长和边界帽干细胞龛中的增殖，导致来自该干细胞龛的神经元后代的衰减。GABA（A）受体的激活导致超极化、细胞体积增加和S期干细胞的积累，从而导致细胞增殖的快速下降。GABA（A）受体通过磷脂酰肌醇-3-OH激酶相关激酶家族的S期检查点激酶和组蛋白变体H2 AX发出信号。该信号通路独立于分化、凋亡和对DNA的明显损伤而严格地调节增殖。这些结果表明，与大多数体细胞相比，这些干细胞中存在根本不同的增殖控制机制，涉及DNA损伤检查点途径中的蛋白质。
Stem cell self- renewal implies proliferation under continued maintenance of multipotency. Small changes in numbers of stem cells may lead to large differences in differentiated cell numbers, resulting in significant physiological consequences. Proliferation is typically regulated in the G1 phase, which is associated with differentiation and cell cycle arrest(1). However, embryonic stem ( ES) cells may lack a G1 checkpoint(2,3). Regulation of proliferation in the 'DNA damage' S/G2 cell cycle checkpoint pathway is known for its role in the maintenance of chromatin structural integrity(4). Here we show that autocrine/paracrine gamma-aminobutyric acid ( GABA) signalling by means of GABA(A) receptors negatively controls ES cell and peripheral neural crest stem ( NCS) cell proliferation, preimplantation embryonic growth and proliferation in the boundary- cap stem cell niche, resulting in an attenuation of neuronal progenies from this stem cell niche. Activation of GABA(A) receptors leads to hyperpolarization, increased cell volume and accumulation of stem cells in S phase, thereby causing a rapid decrease in cell proliferation. GABA(A) receptors signal through S- phase checkpoint kinases of the phosphatidylinositol-3-OH kinase- related kinase family and the histone variant H2AX. This signalling pathway critically regulates proliferation independently of differentiation, apoptosis and overt damage to DNA. These results indicate the presence of a fundamentally different mechanism of proliferation control in these stem cells, in comparison with most somatic cells, involving proteins in the DNA damage checkpoint pathway.