title: Histone H2AX-dependent GABA(A) receptor regulation of stem cell proliferation.
abstract: 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. However, embryonic stem (ES) cells may lack a G1 checkpoint. 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. 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.
authors.affiliation: Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Andäng
authors.forename: Jens
authors.initials: J
authors.lastname: Hjerling-Leffler
authors.forename: Annalena
authors.initials: A
authors.lastname: Moliner
authors.forename: T Kalle
authors.initials: TK
authors.lastname: Lundgren
authors.forename: Gonçalo
authors.initials: G
authors.lastname: Castelo-Branco
authors.forename: Evanthia
authors.initials: E
authors.lastname: Nanou
authors.forename: Ester
authors.initials: E
authors.lastname: Pozas
authors.forename: Vitezslav
authors.initials: V
authors.lastname: Bryja
authors.forename: Sophie
authors.initials: S
authors.lastname: Halliez
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishimaru
authors.forename: Johannes
authors.initials: J
authors.lastname: Wilbertz
authors.forename: Ernest
authors.initials: E
authors.lastname: Arenas
authors.forename: Martin
authors.initials: M
authors.lastname: Koltzenburg
authors.forename: Patrick
authors.initials: P
authors.lastname: Charnay
authors.forename: Abdeljabbar
authors.initials: A
authors.lastname: El Manira
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Ibañez
authors.forename: Patrik
authors.initials: P
authors.lastname: Ernfors
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D001755:Blastocyst / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D002452:Cell Count; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D048429:Cell Size; D004249:DNA Damage; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006657:Histones / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism; D019899:Paracrine Communication; D018408:Patch-Clamp Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006657:Histones; D019869:Phosphatidylinositol 3-Kinases; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C475961:gamma-H2AX protein, mouse