Abstract
Mechanisms controlling the survival of neural precursor cells (NPCs) are critical during brain development, in adults for neuron replenishment, and after transplantation for neuron replacement. This investigation found that glycogen synthase kinase 3 (GSK3) promotes apoptotic signaling in cultured NPCs derived from embryonic mouse brain subjected to two common apoptotic conditions, trophic factor withdrawal and genotoxic stress. Trophic factor withdrawal activated GSK3 and the key apoptosis mediators Bax and caspase-3. Pharmacological inhibition of GSK3 activity produced dramatic reductions in the activation of Bax and caspase-3 and NPC death after trophic factor withdrawal. Trophic factor withdrawal-induced apoptosis was delayed in Bax knock-out NPCs, but GSK3 inhibitors provided additional protection. Genotoxic stress induced by camptothecin treatment of NPCs stabilized p53, which formed a complex with GSK3beta and activated Bax and caspase-3. Camptothecin-induced activation of caspase-3 was reduced by GSK3 inhibitors in both bax(+)(/)(+) and bax(-/-) NPCs. Thus, NPCs are sensitive to loss of trophic factors and genotoxic stress, and inhibitors of GSK3 are capable of enhancing NPC survival.
Highlights
Neural precursor cells (NPCs),2 which through the process of neurogenesis give rise to daughter cells that develop into mature neurons, are vital for brain development and for the maintenance of normal brain function during the lifespan of mammals [1, 2]
The results demonstrate that NPCs die by apoptosis involving Bax and caspase-3 activation after trophic factor withdrawal or DNA damage, and glycogen synthase kinase 3 (GSK3) inhibitors attenuate apoptotic signaling in NPCs exposed to each of these conditions
Characterization of NPCs and Trophic Factor Withdrawal-induced Apoptosis—Isolated NPCs were expanded as neurospheres and plated as monolayers
Summary
Neural precursor cells (NPCs), which through the process of neurogenesis give rise to daughter cells that develop into mature neurons, are vital for brain development and for the maintenance of normal brain function during the lifespan of mammals [1, 2]. 22856 JOURNAL OF BIOLOGICAL CHEMISTRY genesis can theoretically be accomplished by increasing NPC proliferation, differentiation, or survival The latter is a attractive site for intervention because before maturing to functional neurons a significant portion of NPCs is lost due to death by apoptosis, the precise percentage that dies remains uncertain [12,13,14], and after transplantation most NPCs die by apoptosis [15]. Because many NPCs may be lost to apoptosis, GSK3 promotes apoptosis, and GSK3 inhibitors are available to block GSK3-facilitated apoptosis, GSK3 may be a favorable target for bolstering neurogenesis To investigate this possibility with apoptotic conditions that NPCs may encounter either during development or with cytotoxic stresses, we exposed NPCs to trophic factor withdrawal or to the DNA damaging agent camptothecin. The results demonstrate that NPCs die by apoptosis involving Bax and caspase-3 activation after trophic factor withdrawal or DNA damage, and GSK3 inhibitors attenuate apoptotic signaling in NPCs exposed to each of these conditions
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