Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain

Abstract

Nitric oxide (NO) is believed to act as an intercellular signal that regulates synaptic plasticity in mature neurons. We now report that NO also regulates the proliferation and differentiation of mouse brain neural progenitor cells (NPCs). Treatment of dissociated mouse cortical neuroepithelial cluster cell cultures with the NO synthase inhibitor L-NAME or the NO scavenger hemoglobin increased cell proliferation and decreased differentiation of the NPCs into neurons, whereas the NO donor sodium nitroprusside inhibited NPC proliferation and increased neuronal differentiation. Brain-derived neurotrophic factor (BDNF) reduced NPC proliferation and increased the expression of neuronal NO synthase (nNOS) in differentiating neurons. The stimulatory effect of BDNF on neuronal differentation of NPC was blocked by L-NAME and hemoglobin, suggesting that NO produced by the latter cells inhibited proliferation and induced neuronal differentiation of neighboring NPCs. A similar role for NO in regulating the switch of neural stem cells from proliferation to differentiation in the adult brain is suggested by data showing that NO synthase inhibition enhances NPC proliferation and inhibits neuronal differentiation in the subventricular zone of adult mice. These findings identify NO as a paracrine messenger stimulated by neurotrophin signaling in newly generated neurons to control the proliferation and differentiation of NPC, a novel mechanism for the regulation of developmental and adult neurogenesis.

Interactions between the NO-Citrulline Cycle and Brain-derived Neurotrophic Factor in Differentiation of Neural Stem Cells

“…Inhibition of AS in cultured cells blocked production of L-arginine and consequently NO formation (44). NOS inhibition maintained NSC in a proliferative state, thereby suppressing neuronal differentiation; furthermore, L-NAME administration into lateral ventricle of adult mice significantly increased the number of proliferating cells (45). Thus, besides being important for triggering neural differentiation, NO plays an important signaling role in proliferation.…”

Lot1 Is a Key Element of the Pituitary Adenylate Cyclase-activating Polypeptide (PACAP)/Cyclic AMP Pathway That Negatively Regulates Neuronal Precursor Proliferation

“…Feedback pathways exist in diverse neuronal systems, including Drosophila miRNA9a, which regulates sensory organ precursor number by down-regulating Senseless expression (78) or Branchless and Hedgehog pathways that form a positive feedback loop to regulate the onset of neuroblast division (79). In the mammalian brain, nitric oxide acts in a positive feedback loop with brainderived neurotrophic factor to regulate neural progenitor cell proliferation and differentiation (80).…”

Blocking p55PIK signaling inhibits proliferation and induces differentiation of leukemia cells

“…Immunostaining with FITC-labeled anti-Cd11b antibody was performed as described. 26 Shown are representative histograms from an individual experiment. Number shown in each box is the percentage of cells with Cd11b þ expression (M1).…”

“…Immunostaining with FITC-labeled antiCd11b and PE-labeled anti-Cd14 antibodies were performed as described. 26 Shown are representative histograms from an individual experiment. Number shown is the percentage of cells with Cd11b þ (event numbers in upper right and upper left area/total events) and Cd14 þ expression (event numbers in upper right and lower right areas/ total events).…”