Neurogenesis proceeds in two major regions of the adult mammalian CNS. The subependymal zone (SEZ) at the lateral ventricles harbours stem cells that continuously provide new neurons for the olfactory bulb, whereas progenitors situated in the subgranular layer of the hippocampus (SGL) continuously produce new granule cells. Neurogenesis involves a variety of cellular events including cell proliferation, cell fate determination, migration, differentiation, integration and survival of young neurons. These processes are controlled by a symphony of cellular signals. We have investigated the functional role of nucleotides in the control of adult neurogenesis in the murine brain. Once released from cells to the extracellular milieu – nucleotides represent key mediators of cellular communication both in the CNS and in other tissues. They can act on a multiplicity of receptors (G protein-coupled P2Y and ionotropic P2X receptors) that differ regarding agonist specificity and the induced intracellular signal pathways. Nucleotide signalling is terminated or modulated by cell surface-located nucleotide-hydrolyzing enzymes (ectonucleotidases). We have previously shown that ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2), an enzyme that hydrolyzes extracellular nucleoside triphosphates to the respective nucleoside monophosphates, is specifically expressed by neural progenitors in the SEZ and SGL and that functional P2Y receptors are expressed in primary culture of adult neural stem cells (neurospheres or adherent cell cultures) (1-3). Furthermore both nucleotides and the growth factor EGF stimulated in vitro progenitor cell proliferation and migration and induced converging intracellular signalling pathways, implicating a possible role for nucleotides in adult neurogenesis (3-5). Deletion of NTPDase2 should increase the extracellular concentrations of P2 receptor agonists such as ATP or UTP in the vicinity of the NTPDase2-depleted cells and thus enhance any nucleotide-mediated effect on neurogenesis. Proliferation of neural progenitors cells derived from NTPDase2 knockout mice and cultured as neurospheres in vitro was enhanced by a factor of two as compared to wild type controls. We then investigated potential in vivo effects of NTPDase2 deletion. Mice were subjected to time-controlled protocols of intraperitoneal BrdU application and the survival of BrdU-labelled cells was investigated in tissue sections two hours (proliferation and short term survival) and four weeks (long-term survival) after the end of BrdU application. As compared to wild type controls, progenitor cell proliferation was increased twofold in both the SEZ and the dentate gyrus in the NTPDase2 knockout animals. However, young neuron survival in the olfactory bulb and in the hippocampus was not significantly altered. These data suggest that NTPDase2 knockout, presumably associated with an increase in extracellular nucleotide concentrations in the neurogenic niches, enhanced progenitor cell proliferation. Nucleotides would, however, not support long term survival of young neurons. The data provide first in vivo evidence for a contribution of purinergic signalling to the control of adult neurogenesis.