Neural stem cells (NSCs) continuously produce new neurons within the adult mammalian hippocampus. and ERK pathways that control cell fate and proliferation. These findings identify VEGF-C/VEGFR3 signaling as a specific regulator of NSC activation and neurogenesis in mammals. Graphical abstract INTRODUCTION The adult mammalian brain continuously produces new neurons in two discrete regions the subventricular zone (SVZ) lining the ventricles and the dentate gyrus (DG) of the hippocampus (Altman and Das 1965 Doetsch et al. 1999 In rodents hippocampal neurogenesis is enhanced by external factors including an enriched environment and voluntary running exercise (Brown et al. 2003 Vivar and van Praag 2013 A decline in hippocampal neurogenesis occurs with age and may underlie cognitive and mood alterations associated with aging and Alzheimer’s disease (Lazarov et al. 2010 Mu and Gage 2011 Hippocampal neurogenesis occurs within the subgranular zone (SGZ) of the DG and is initiated by neural stem cells Huzhangoside D (NSCs) which Huzhangoside D undergo a series of divisions to generate new granular layer interueurons that integrate into the hippocampal circuitry (Kempermann et al. 2004 NSCs include a quiescent population which are radial glia-like cells (RGLs) (or type-1 cells) that are characterized by the expression of Nestin GFAP Sox2 and Hes5 (Bonaguidi et al. 2011 Encinas et al. 2011 Lugert et al. 2010 Suh et al. 2007 NSC activation is upon Ascl1 regulation (Andersen et al. 2014 and leads Huzhangoside D to generate proliferative progenitors known as intermediate progenitors (IPCs) which in turn give rise to committed neuronal progenitors (neuroblasts). Whereas the steps of hippocampal neuron formation have been well characterized (Bonaguidi et al. 2012 Kempermann et al. 2004 the molecular mechanisms controlling this cellular progression remain poorly understood. Several signaling pathways are known to maintain hippocampal NSC quiescence through inhibition of cell proliferation. Conditional disruption of the genes encoding BMP2 and 4 sFRP3 Notch/RBP-J and REST in RGLs all result in rapid activation of NSC division leading to a transient increase in IPC numbers and production of new adult hippocampal neurons (Ehm et al. 2010 Gao et al. 2011 Jang et al. 2013 Mira et al. 2010 In contrast to these repressors of NSC activation only a few positive regulators of NSC division and progenitor cell production are known. These include sonic hedgehog/smoothened and BDNF/TrkB but both of these signaling pathways are also active in other subpopulations of the hippocampal niche (Li et at. 2008 Machold et al. 2003 Identification of NSC-selective positive regulators should allow prolonging or enhancing neurogenesis during aging and improve the efficacy Huzhangoside D of NSC-based repair therapies especially in older patients. Vascular endothelial growth factors (VEGFs) and their high-affinity tyrosine kinase receptors (VEGFRs) are potent regulators of the growth and maintenance of vascular and neural cells (Eichmann and Thomas 2013 Zacchigna et al. 2008 In the hippocampus VEGF-A increases angiogenesis neurogenesis and neuronal plasticity (During and Cao 2006 Fournier and Duman 2012 Licht and Keshet 2013 However it is not clear whether VEGF-A enhances neurogenesis directly through Rabbit polyclonal to GAPDH.Glyceraldehyde 3 phosphate dehydrogenase (GAPDH) is well known as one of the key enzymes involved in glycolysis. GAPDH is constitutively abundant expressed in almost cell types at high levels, therefore antibodies against GAPDH are useful as loading controls for Western Blotting. Some pathology factors, such as hypoxia and diabetes, increased or decreased GAPDH expression in certain cell types. its receptors VEGFR1 and 2 on neural cells or indirectly through factors released from newly formed blood vessels. The related growth factor VEGF-C is a potent regulator of lymphangiogenesis (Lohela et al. 2009 VEGF-C also induces angiogenesis but only weakly as expression of its receptor VEGFR3 is mainly restricted to tip cells at the extremities of growing blood vessels (Tammela et al. 2008 In the brain we have previously shown that VEGF-C stimulates neurogenesis via direct cell-autonomous actions of VEGFR3 in neural cells. Deletion of impairs neural development in both and mouse embryonic brains and conditional deletion of within NSCs affects neurogenesis in the adult mouse SVZ (Calvo et al. 2011 Le Bras et al. 2006 We hypothesized that VEGF-C-VEGFR3 signaling might affect hippocampal NSCs in mice and humans thereby controlling neurogenesis. Here we examined the role of VEGFR3 and its mechanism of action in adult.