No abstract

Multipotent cortical progenitor cells differentiate into neurons and glial cells during development; however, mechanisms governing the specification of progenitors to a neuronal fate are not well understood. Although both extrinsic and intrinsic factors regulate this process, little is known about kinase signaling mechanisms that direct neuronal fate. Here, we report that extracellular signalregulated kinase (ERK) 5 is expressed and active in proliferating cortical progenitors. Lentiviral gene delivery of a dominant negative ERK5 or dominant negative MAP kinase kinase 5 reduced the number of neurons generated from rat cortical progenitor cells in culture, whereas constitutive activation of ERK5 increased the production of neurons. Furthermore, when cortical progenitor cells were treated with ciliary neurotrophic factor, which induces precocious glial differentiation, ERK5 activation still promoted neuronal fate while suppressing glial differentiation. Our data also indicate that ERK5 does not directly regulate proliferation or apoptosis of cultured cortical progenitors. We conclude that ERK5 is necessary and sufficient to stimulate the generation of neurons from cortical progenitors. These results suggest a previously uncharacterized function for ERK5 signaling during brain development and raise the interesting possibility that extrinsic factors may instruct cortical progenitors to become neurons by activating the ERK5 pathway.neural progenitor cell ͉ neural stem cell ͉ neurogenesis M ultipotent neural progenitor cells can differentiate into neurons or glia depending on developmental cues and environmental signals. Neuronal differentiation proceeds by a two-step process: the initial commitment of the progenitors to a neuronal fate, followed by cell cycle exit and terminal differentiation of the committed precursors into mature neurons (1). The specification of cortical progenitors to a neuronal fate requires a coordinated expression of the proneural basic helix-loop-helix (bHLH) transcription factors (2, 3). In addition to this intrinsic program, extrinsic factors also regulate fate choice of neural progenitor cells (4, 5).ERK5 is a member of the mitogen-activated protein (MAP) kinase family (6). In neurons, ERK5 is activated by neurotrophins including BDNF but not by Ca 2ϩ or cAMP (7-9). ERK5 is phosphorylated and activated by MAP kinase kinase (MEK) 5 but not by MEK1 or MEK2 (6). MEK5 is specific for ERK5 and does not phosphorylate or activate other MAP kinases (7, 10).ERK5 is widely expressed in many tissues with the highest levels in brain (11,12). In this study, we performed a detailed analysis of ERK5 expression during rat cortical development and discovered that it is expressed as early as embryonic day (E) 11 and is active during cortical neurogenic period. Furthermore, ERK5 is expressed in nestin ϩ and BrdU ϩ cortical progenitor cells in cultures. Its abundant expression in proliferating progenitor cells suggests that ERK5 may play a role in cortical progenitor cell biology that may include proliferatio...

Mechanistic studies underlying dopaminergic neuron death may identify new drug targets for the treatment of Parkinson disease (PD). Epidemiological studies have linked pesticide exposure to increased risk for sporadic PD. Here, we investigated the role of c-Jun N-terminal kinase 3 (JNK3), a neural-specific JNK isoform, in dopaminergic neuron death induced by the pesticides rotenone and paraquat. The role of JNK3 was evaluated using RNA silencing and gene deletion to block JNK3 signaling. Using an antibody that recognizes all isoforms of activated JNKs, we found that paraquat and rotenone stimulate JNK phosphorylation in primary cultured dopaminergic neurons. In cultured neurons transfected with Jnk3-specific siRNA and in neurons from Jnk3−/− mice, JNK phosphorylation was nearly abolished, suggesting that JNK3 is the main JNK isoform activated in dopaminergic neurons by these pesticides. Paraquat- and rotenone-induced death of dopaminergic neurons was also significantly reduced by Jnk3 siRNA or Jnk3 gene deletion and deletion of the Jnk3 gene completely attenuated paraquat-induced dopaminergic neuron death and motor-deficits in vivo. Our data identify JNK3 as a common and critical mediator of dopaminergic neuron death induced by paraquat and rotenone, suggesting that it is a potential drug target for PD treatment.

Recent studies have shown that inhibition of adult neurogenesis impairs the formation of hippocampus-dependent memory. However, it is not known whether increasing adult neurogenesis affects the persistence of hippocampus-dependent long-term memory. Furthermore, signaling mechanisms that regulate adult neurogenesis are not fully defined. We recently reported that the conditional and targeted knock-out of ERK5 MAP kinase in adult neurogenic regions of the mouse brain attenuates adult neurogenesis in the hippocampus and disrupts several forms of hippocampus-dependent memory. Here, we developed a gain-of-function knock-in mouse model to specifically activate endogenous ERK5 in the neurogenic regions of the adult brain. We report that the selective and targeted activation of ERK5 increases adult neurogenesis in the dentate gyrus by enhancing cell survival, neuronal differentiation, and dendritic complexity. Conditional ERK5 activation also improves the performance of challenging forms of spatial learning and memory and extends hippocampus-dependent long-term memory. We conclude that enhancing signal transduction of a single signaling pathway within adult neural stem/progenitor cells is sufficient to increase adult neurogenesis and improve the persistence of hippocampus-dependent memory. Furthermore, activation of ERK5 may provide a novel therapeutic target to improve long-term memory.