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The Journal of Neuroscience, June 15, 2003, 23(12):5149-5160
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Endogenously Produced Neurotrophins Regulate Survival and Differentiation of Cortical Progenitors via Distinct Signaling Pathways
Fanie Barnabé-Heider1,2 andFreda D. Miller1,2 1Center for Neuronal Survival and Brain Tumor Research Center, Montreal Neurological Institute, McGill University, Montreal, Canada H3A 2B4, and 2Hospital for Sick Children Research Institute, University of Toronto, Toronto, Canada M5G 1X8
Cultured embryonic cortical progenitor cells will mimic the temporal differentiation pattern observed in vivo, producing neurons first and then glia. Here, we investigated the role of two endogenously produced growth factors, the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 (NT-3), in the early progenitor-to-neuron transition. Cultured cortical progenitors express BDNF and NT-3, as well as their receptors TrkB (tyrosine kinase receptor B) and TrkC. Inhibition of these endogenously expressed neurotrophins using function-blocking antibodies resulted in a marked decrease in the survival of cortical progenitors, accompanied by decreased proliferation and inhibition of neurogenesis. Inhibition of neurotrophin function also suppressed the downstream Trk receptor signaling pathways, PI3-kinase (phosphatidyl inositol-3-kinase) and MEK—ERK (MAP kinase kinase—extracellular signal-regulated kinase), indicating the presence of autocrine—paracrine neurotrophin:Trk receptor signaling in these cells. Moreover, specific inhibition of these two Trk signaling pathways led to distinct biological effects; inhibition of PI3-kinase decreased progenitor cell survival, whereas inhibition of MEK selectively blocked the generation of neurons, with no effects on survival or proliferation. Thus, neurotrophins made by cortical progenitor cells themselves signal through the TrkB and TrkC receptors to mediate cortical progenitor cell survival and neurogenesis via two distinct downstream signaling pathways.
Key words: MAPK; PI3-kinase; Akt; BDNF; NT-3; FGF2; neurogenesis; gliogenesis; neural apoptosis; proliferation
Received Dec. 2, 2002; revised Feb. 26, 2003; accepted Mar. 28, 2003.
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