Nature：一个控制干细胞周期的新机制

生物谷报道：干细胞的自我更新涉及在持续增殖下对多能性的保持。胚胎干细胞的增殖过去被认为是结构性的，是不受调控的，因为正常细胞周期调控机制在这些细胞中是不工作的。现在，Andäng等人提出证据表明，在胚胎干细胞中和在其他特定组织中的干细胞类型中，存在一个从根本上来说是新的细胞周期调控机制。按照这一机制，内生GABA受体信号通过一个涉及细胞周期蛋白的机制来控制细胞增殖，而这些细胞周期蛋白以前被与细胞DNA检查点通道联系在一起。

生物谷推荐英文原文：

Nature 451, 460-464 (24 January 2008) | doi:10.1038/nature06488; Received 24 August 2007; Accepted 22 November 2007; Published online 9 January 2008

Histone H2AX-dependent GABAA receptor regulation of stem cell proliferation

Michael Andäng1, Jens Hjerling-Leffler1, Annalena Moliner2, T. Kalle Lundgren1, Gonçalo Castelo-Branco3, Evanthia Nanou2, Ester Pozas1, Vitezslav Bryja1,7, Sophie Halliez5, Hiroshi Nishimaru2, Johannes Wilbertz4, Ernest Arenas1, Martin Koltzenburg6, Patrick Charnay5, Abdeljabbar El Manira2, Carlos F. Ibañez2 & Patrik Ernfors1

Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics,
Department of Neuroscience,
Laboratory of Molecular Neurodevelopment, Department of Neuroscience,
Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
INSERM, U 784, École Normale Supérieure, 75230 Paris Cedex 05, France
Neural Plasticity Unit, Institute of Child Health, University College London, London WCIE 6BT, UK
Present address: Institute of Biophysics Academy of Sciences of the Czech Republic and Institute of Experimental Biology, Faculty of Science, Masaryk University, 603 65 Brno, Czech Republic.

Correspondence to: Patrik Ernfors1 Correspondence and requests for materials should be addressed to P.E. (Email: patrik.ernfors@ki.se).

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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 arrest1. However, embryonic stem (ES) cells may lack a G1 checkpoint2, 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 integrity4. Here we show that autocrine/paracrine gamma -aminobutyric acid (GABA) signalling by means of GABAA 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 GABAA receptors leads to hyperpolarization, increased cell volume and accumulation of stem cells in S phase, thereby causing a rapid decrease in cell proliferation. GABAA 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.