Mitogen‐ and stress‐activated kinases regulate progenitor cell proliferation and neuron development in the adult dentate gyrus

Choi, Yun Sik; Karelina, Kate; Alzate‐Correa, Diego; Hoyt, Kari R.; Impey, Soren; Arthur, J. Simon C.; Obrietan, Karl

doi:10.1111/jnc.12035

Cited by 18 publications

(28 citation statements)

References 62 publications

(109 reference statements)

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“…Further, fluorescent immunolabeling for pMSK1 and the progenitor cell marker Sox-2, indicated that the activated form of the kinase is expressed in progenitor cell populations of the SGZ at 2 DPI (Figure 1E). These data, coupled with prior work from our lab (Choi et al, 2012) showing MSK1 expression in SGZ progenitor cells, strongly suggest that ischemia triggers MSK1 activation in progenitor cells…”

Section: Resultssupporting

confidence: 75%

“…Using the same set of DCX/BrdU labeled tissues, co-labeled cells were qualitatively categorized into stages of neuronal development based on morphology (Figure 5). Stages were defined as previously reported (Choi et al, 2012). Briefly, stage 1 cells were defined as having no processes; stage 2 cells were defined as having short processes extending into the GCL; stage 3 cells were defined as those extending long processes into the molecular layer; and stage 4 cells were defined as having long processes and branches extending into the molecular layer.…”

Section: Resultsmentioning

confidence: 99%

“…MSK1/2 are a nuclear-localized family of serine/threonine kinases that tightly regulate the transactivational potential of numerous transcription factors (Deak et al, 1998, Wiggin et al, 2002, Hauge and Frödin, 2006). We recently reported that both basal and seizure-evoked progenitor cell proliferation, as well as adult neurogenesis, are disrupted in MSK1/2 null mice (Choi et al, 2012). In a separate line of work, the deletion of MSK1 was found to impair environmental enrichment-induced hippocampal neuron plasticity, as well as cognition (Karelina et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Mitogen and stress-activated kinases 1/2 regulate ischemia-induced hippocampal progenitor cell proliferation and neurogenesis

et al. 2015

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Pathophysiological conditions such as cerebral ischemia trigger the production of new neurons from the neurogenic niche within the subgranular zone (SGZ) of the dentate gyrus. The functional significance of ischemia-induced neurogenesis is believed to be the regeneration of lost cells, thus contributing to post-ischemia recovery. However, the cell signaling mechanisms by which this process is regulated are still under investigation. Here, we investigated the role of mitogen and stress-activated protein kinases (MSK1/2) in the regulation of progenitor cell proliferation and neurogenesis after cerebral ischemia. Using the endothelin-1 model of ischemia, wild type (WT) and MSK1−/−/MSK2−/− (MSK dKO) mice were injected with BrdU and sacrificed 2 days, 4 weeks, or 6 weeks later for the analysis of progenitor cell proliferation, neurogenesis, and neuronal morphology, respectively. We report a decrease in SGZ progenitor cell proliferation in MSK dKO mice compared to WT mice. Moreover, MSK dKO mice exhibited reduced neurogenesis and a delayed maturation of ischemia-induced newborn neurons. Further, structural analysis of neuronal arborization revealed reduced branching complexity in MSK dKO compared to WT mice. Taken together, this dataset suggests that MSK1/2 plays a significant role in the regulation of ischemia-induced progenitor cell proliferation and neurogenesis. Ultimately, revealing the cell signaling mechanisms that promote neuronal recovery will lead to novel pharmacological approaches for the treatment of neurodegenerative diseases such as cerebral ischemia.

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Section: Resultssupporting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitogen and stress-activated kinases 1/2 regulate ischemia-induced hippocampal progenitor cell proliferation and neurogenesis

et al. 2015

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“…Further, MAPK signaling is rapidly activated by cerebral ischemia (Gu et al, 2001; Wu et al, 2000) and regulates both cytoplasmic and nuclear targets to promote cell growth, differentiation and apoptosis (Pan et al, 2012; Zhang and Liu, 2002). Regulation of these processes occurs via both direct ERK phosphorylation of transcription factors (Zhang and Liu, 2002) and also via phosphorylation of downstream effector kinases such as the mitogen and stress-activated kinase (MSKs) and ribosomal S6 kinases (RSKs) (Choi et al, 2012; Hauge and Frödin, 2006; Karelina et al, 2012; Yves et al, 2012), which are the focus of the current study.…”

Section: Introductionmentioning

confidence: 99%

Ribosomal S6 kinase regulates ischemia-induced progenitor cell proliferation in the adult mouse hippocampus

Karelina

Alzate‐Correa

Obrietan

2014

Experimental Neurology

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Ischemia-induced progenitor cell proliferation is a prominent example of the adult mammalian brain’s ability to regenerate injured tissue resulting from pathophysiological processes. In order to better understand and exploit the cell signaling mechanisms that regulate ischemia-induced proliferation, we examined the role of the p42/44 mitogen-activated protein kinase (MAPK) cascade effector ribosomal S6 kinase (RSK) in this process. Here, using the endothelin-1 ischemia model in wild type mice, we show that the activated form of RSK is expressed in the progenitor cells of the subgranular zone (SGZ) after intrahippocampal cerebral ischemia. Further, RSK inhibition significantly reduces ischemia-induced SGZ progenitor cell proliferation. Using the neurosphere assay, we also show that both SGZ- and subventricular zone (SVZ)-derived adult neural stem cells (NSC) exhibit a significant reduction in proliferation in the presence of RSK and MAPK inhibitors. Taken together, these data reveal RSK as a regulator of ischemia-induced progenitor cell proliferation, and as such, suggest potential therapeutic value may be gained by specifically targeting the regulation of RSK in the progenitor cell population of the SGZ.

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“…Moreover, blood-brain barrier (BBB) leakage has been reported following pilocarpine-induced SE, which may provide an environment for peripheral leukocyte infiltration. On the other hand, when examined 2 days after SE, pilocarpine-induced SE increased progenitor cell proliferation in the subgranular zone through insulin-like growth factor-1 (IGF-1)-ERK-MSK signaling pathways [4,5]. Considering the distinct roles of Tbr2 in proliferation and differentiation of progenitor cells as well as in the infiltration of CD8+ T cells and natural killer cells, it may be interesting to investigate the intervention of Tbr2 in progenitor cell proliferation and/or immune reaction following SE.…”

Section: Introductionmentioning

confidence: 99%

Expression of Tbr2 in the Hippocampus Following Pilocarpine-induced Status Epilepticus

Choi¹

2013

Journal of Life Science

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T-box transcription factor 2 (Tbr2) is a member of the T-box family of transcription factors and it plays an important role in brain development, progenitor cell proliferation, and the modulation of differentiation and function in immune cells, such as CD8+ T cells and natural killer cells. This study aims to elucidate the involvement of Tbr2 in the pathophysiological events following pilocarpine-induced status epilepticus in mice. Status epilepticus resulted in prominent neuronal cell death in discrete brain regions, such as CA3, the hilus, and the piriform cortex. Interestingly, when the immunoreactivity of Tbr2 was examined two days after status epilepticus, it was transiently increased in CA3 and in the piriform cortex. Tbr2-positive cells in CA3 and the piriform cortex were double-labeled with CD11b, a marker of microglia and a subset of white blood cells, such as monocytes, CD8+ T cells, and natural killer cells. Moreover, the double-labeled cells with Tbr2 and CD11b showed amoeboid morphology, and this data indicates that Tbr2-expressing cells may be reactive microglia or infiltrating white blood cells. Furthermore, clustered Tbr2-positive cells were observed in the platelet endothelial cell adhesion molecule-1 (PECAM-1)-positive blood vessels near the CA3 area, which suggests that Tbr2-positive cells may be infiltrating the white blood cells. Based on this data, this study is the first to indicate the involvement of Tbr2 in neuropathophysiology in status epilepticus.Key words : CD11b, hippocampus, pilocarpine, status epilepticus, T-box transcription factor 2 (Tbr2) *Corresponding author *Tel : +82-53-850-2561, Fax : +82-53-359-6820 *E-mail : tiana@cu.ac.kr This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. IntroductionThe T-box family of transcription factor genes play an important role in early embryonic cell fate decisions, development of extraembryonic structures, embryonic patterning, and organogenesis [21]. Among these genes, T-box transcription factor 2 (Tbr2), also known as eomesodermin (Eomes), comprises the Tbr2 subfamily with Tbr1 and Tbx21 (T-bet), and regulates the differentiation of excitatory projection neurons and retinal ganglion cells [11,17]. In addition, Tbr2 is required for the maintenance of excitatory-inhibitory balance in the olfactory bulb circuitry [20,26] Tbr2 is also expressed in a subset of white blood cells, such as CD8+ T cells and natural killer cells. In CD8+ T cells, Tbr2 with T-bet induces the expression of granzyme B, perforin, and interferon-γ (IFN-γ), and both transcription factors are thought to be involved in differentiation of effector and memory T cells [9,13,16,22]. Interestingly, the amount of memory CD8+ T cells decreased when Tbr2 gene was deleted whereas it increased when T-bet was absent [3]. Additionally, ...

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Mitogen‐ and stress‐activated kinases regulate progenitor cell proliferation and neuron development in the adult dentate gyrus

Cited by 18 publications

References 62 publications

Mitogen and stress-activated kinases 1/2 regulate ischemia-induced hippocampal progenitor cell proliferation and neurogenesis

Mitogen and stress-activated kinases 1/2 regulate ischemia-induced hippocampal progenitor cell proliferation and neurogenesis

Ribosomal S6 kinase regulates ischemia-induced progenitor cell proliferation in the adult mouse hippocampus

Expression of Tbr2 in the Hippocampus Following Pilocarpine-induced Status Epilepticus

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