Coordinate pathways for nucleotide and EGF signaling in cultured adult neural progenitor cells

The adult subventricular zone (SVZ) contains astrocyte-like stem cells capable of generating new neurons for the olfactory bulb. Adult neurogenesis is driven by a variety of signal systems that can induce synergistic or opposing cellular responses. It is therefore important to gain insight into the underlying downstream signaling pathways. We have previously shown that the nucleotides ADPbetaS and UTP induce rapid Ca2+ transients in cultured SVZ-derived adult neural progenitors and augment growth-factor-mediated progenitor cell proliferation. Here, we investigated signaling pathways elicited by ADPbetaS, UTP and epidermal growth factor (EGF). All three agonists elicit ERK1/2 and CREB phosphorylation but the temporal characteristics differ between the nucleotides and EGF. Differentiation of the progenitors alters the receptor profile. Oligodendrocytes and young neurons, but not astrocytes, lose responsiveness to the agonists. Inhibition experiments are indicative of an ADPbetaS-elicited EGF receptor transactivation. Whereas UTP acts via the P2Y2 receptor, ADPbetaS exerts its function via the P2Y1 receptor and the P2Y13 receptor. Our data demonstrate that nucleotides and EGF induce converging, but also differential, intracellular signaling pathways and suggest that they carry the potential to act synergistically in the control of cell proliferation and cell survival in adult neurogenesis.