title: NTPDase2 and purinergic signaling control progenitor cell proliferation in neurogenic niches of the adult mouse brain.
abstract: Nerve cells are continuously generated from stem cells in the adult mammalian subventricular zone (SVZ) and hippocampal dentate gyrus. We have previously noted that stem/progenitor cells in the SVZ and the subgranular layer (SGL) of the dentate gyrus express high levels of plasma membrane-bound nucleoside triphosphate diphosphohydrolase 2 (NTPDase2), an ectoenzyme that hydrolyzes extracellular nucleoside diphosphates and triphosphates. We inferred that deletion of NTPDase2 would increase local extracellular nucleoside triphosphate concentrations perturbing purinergic signaling and boosting progenitor cell proliferation and neurogenesis. Using newly generated mice globally null for Entpd2, we demonstrate that NTPDase2 is the major ectonucleotidase in these progenitor cell-rich areas. Using BrdU-labeling protocols, we have measured stem cell proliferation and determined long-term survival of cell progeny under basal conditions. Brains of Entpd2 null mice revealed increased progenitor cell proliferation in both the SVZ and the SGL. However, this occurred without noteworthy alterations in long-term progeny survival. The hippocampal stem cell pool and the pool of the intermediate progenitor type-2 cells clearly expanded. However, substantive proportions of these proliferating cells were lost during expansion at around type-3 stage. Cell loss was paralleled by decreases in cAMP response element-binding protein phosphorylation in the doublecortin-positive progenitor cell population and by an increase in labeling for activated caspase-3 levels. We propose that NTPDase2 has functionality in scavenging mitogenic extracellular nucleoside triphosphates in neurogenic niches of the adult brain, thereby acting as a homeostatic regulator of nucleotide-mediated neural progenitor cell proliferation and expansion.
authors.affiliation: Institute of Cell Biology and Neuroscience, Goethe-University, Frankfurt, Germany.
authors.forename: Kristine
authors.initials: K
authors.lastname: Gampe
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stefani
authors.forename: Klaus
authors.initials: K
authors.lastname: Hammer
authors.forename: Peter
authors.initials: P
authors.lastname: Brendel
authors.forename: Alexandra
authors.initials: A
authors.lastname: Pötzsch
authors.forename: Grigori
authors.initials: G
authors.lastname: Enikolopov
authors.forename: Keiichi
authors.initials: K
authors.lastname: Enjyoji
authors.forename: Amparo
authors.initials: A
authors.lastname: Acker-Palmer
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.forename: Herbert
authors.initials: H
authors.lastname: Zimmermann
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D007150:Immunohistochemistry; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology; D015398:Signal Transduction; D055153:Stem Cell Niche / Q000502:physiology*
chemical_list: D000251:Adenosine Triphosphatases; C027201:ectoATPase
keywords: Adenosine 5′-triphosphate; Adult neurogenesis; Ectonucleotidase; Hippocampus; Neural stem cell; Proliferation; Subventricular zone