Histone H2AX-dependent GABA(A) receptor regulation of stem cell proliferation

• Authors: ANDÄNG Michael; HJERLING-LEFFLER Jens; MOLINER Annalena; LUNDGREN T. Kalle; CASTELO-BRANCO Goncalo; NANOU Evanthia; POZAS Ester; BRYJA Vítězslav; HALLIEZ Sophie; NISHIMARU Hiroshi; WILBERTZ Johannes; ARENAS Ernest; KOLTZENBURG Martin; CHARNAY Patrick; EL MANIRA Abdeljabbar; IBANEZ Carlos F.; ERNFORS Patrik
• Year of publication: 2008
• Type: Article in Periodical
• Magazine / Source: Nature
• MU Faculty or unit: Faculty of Science
• Field: Genetics and molecular biology
• Keywords: GABA; STEM CELLS; H2AX
• Description: Here we provide evidence that an auto/paracrine gama-amino butyric acid (GABA) signaling via GABAA receptors negatively controls embryonic stem (ES) cell and peripheral neural crest stem (NCS) cell proliferation, preimplantation embryonic growth as well as proliferation in the boundary cap stem cell niche, resulting in an attenuation of neuronal progenies from this niche. GABAA receptor activation hyperpolarizes the membrane potential, increase cell volume and cause accumulation of stem cells in the cell cycle S-phase, thereby causing a rapid reduction in cell proliferation. Activated GABAA receptors signal through S-phase checkpoint kinases of the PI3K related kinase (PIKK) family resulting in phosphorylation of the histone variant H2AX, an event that is required for the effects of GABA on stem cell proliferation. This signaling pathway is a critical regulator of proliferation independently of multipotency, apoptosis and overt DNA damage.