1. Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics,
2. Department of Neuroscience,
3. Laboratory of Molecular Neurodevelopment, Department of Neuroscience,
4. Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
5. INSERM, U 784, École Normale Supérieure, 75230 Paris Cedex 05, France
6. Neural Plasticity Unit, Institute of Child Health, University College London, London WCIE 6BT, UK
7. 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).

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 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 integrity⁴. Here we show that autocrine/paracrine -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.

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