Histone H2AX-dependent GABAA receptor regulation of stem cell proliferation

• Published in: Nature (London) 2008-01, Vol.451 (7177), p.460-464
• Main Authors: Andäng, Michael, Hjerling-Leffler, Jens, Moliner, Annalena, Lundgren, T. Kalle, Castelo-Branco, Gonçalo, Nanou, Evanthia, Pozas, Ester, Bryja, Vitezslav, Halliez, Sophie, Nishimaru, Hiroshi, Wilbertz, Johannes, Arenas, Ernest, Koltzenburg, Martin, Charnay, Patrick, Manira, Abdeljabbar El, Ibañez, Carlos F., Ernfors, Patrik
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Cell cycle; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cell proliferation; Cellular biology; Deoxyribonucleic acid; DNA; DNA damage; Fundamental and applied biological sciences. Psychology; Histones; Humanities and Social Sciences; letter; Molecular and cellular biology; multidisciplinary; Neurotransmitter receptors; Neurotransmitters; Physiological aspects; Physiology; Science; Science (multidisciplinary); Stem cells
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature06488

Stem cell renewal Stem cell self-renewal involves the maintenance of pluripotency under continued proliferation. Proliferation of embryonic stem cells was thought to be constitutive and not to be regulated, because the normal cell cycle regulatory mechanism is not active in these cells. Now Andäng et al . present evidence for a fundamentally new mechanism of cell cycle regulation operating in embryonic stem cells and in other tissue-specific stem cell types. In it, endogenous GABA receptor signalling controls cell proliferation via a mechanism that involves cell cycle proteins previously associated with the cellular DNA damage checkpoint pathway. The basis of regulation of proliferation of pluripotent embryonic stem cells has been unclear. It is found that endogenous GABA receptor signalling controls proliferation of embryonic stem cells and other tissue-specific stem cell types via a mechanism that involves cell cycle proteins previously associated with cellular DNA damage responses. 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 γ-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 proliferati