title: Extracellular nucleotide signaling in adult neural stem cells: synergism with growth factor-mediated cellular proliferation.
abstract: We have previously shown that the extracellular nucleoside triphosphate-hydrolyzing enzyme NTPDase2 is highly expressed in situ by stem/progenitor cells of the two neurogenic regions of the adult murine brain: the subventricular zone (type B cells) and the dentate gyrus of the hippocampus (residual radial glia). We explored the possibility that adult multipotent neural stem cells express nucleotide receptors and investigated their functional properties in vitro. Neurospheres cultured from the adult mouse SVZ in the presence of epidermal growth factor and fibroblast growth factor 2 expressed the ecto-nucleotidases NTPDase2 and the tissue non-specific isoform of alkaline phosphatase, hydrolyzing extracellular ATP to adenosine. ATP, ADP and, to a lesser extent, UTP evoked rapid Ca(2+) transients in neurospheres that were exclusively mediated by the metabotropic P2Y(1) and P2Y(2) nucleotide receptors. In addition, agonists of these receptors and low concentrations of adenosine augmented cell proliferation in the presence of growth factors. Neurosphere cell proliferation was attenuated after application of the P2Y(1)-receptor antagonist MRS2179 and in neurospheres from P2Y(1)-receptor knockout mice. In situ hybridization identified P2Y(1)-receptor mRNA in clusters of SVZ cells. Our results infer nucleotide receptor-mediated synergism that augments growth factor-mediated cell proliferation. Together with the in situ data, this supports the notion that extracellular nucleotides contribute to the control of adult neurogenesis.
authors.affiliation: Biocenter, J.W. Goethe-University, AK Neurochemistry, Frankfurt am Main, Germany.
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Mishra
authors.forename: Norbert
authors.initials: N
authors.lastname: Braun
authors.forename: Varsha
authors.initials: V
authors.lastname: Shukla
authors.forename: Marc
authors.initials: M
authors.lastname: Füllgrabe
authors.forename: Christof
authors.initials: C
authors.lastname: Schomerus
authors.forename: Horst-Werner
authors.initials: HW
authors.lastname: Korf
authors.forename: Christian
authors.initials: C
authors.lastname: Gachet
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ikehara
authors.forename: Jean
authors.initials: J
authors.lastname: Sévigny
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.forename: Herbert
authors.initials: H
authors.lastname: Zimmermann
mesh_terms: D000241:Adenosine / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2; D015398:Signal Transduction; D014544:Uridine Triphosphate / Q000494:pharmacology
chemical_list: D007527:Isoenzymes; C111914:N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate; C546383:P2ry1 protein, mouse; C546386:P2ry2 protein, mouse; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2; D016222:Fibroblast Growth Factor 2; D000244:Adenosine Diphosphate; D004815:Epidermal Growth Factor; D000255:Adenosine Triphosphate; D000469:Alkaline Phosphatase; D000251:Adenosine Triphosphatases; C027201:ectoATPase; D000241:Adenosine; D002118:Calcium; D014544:Uridine Triphosphate