Neurogenin 1 Mediates Erythropoietin Enhanced Differentiation of Adult Neural Progenitor Cells

Wang, Lei; Zhang, Zheng G.; Zhang, Rui L.; Jiao, Zhong Xian; Wang, Ying; LeTourneau, Yvonne; Gregg, Sara R; Chopp, Michael

doi:10.1038/sj.jcbfm.9600215

Cited by 53 publications

(44 citation statements)

References 35 publications

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“…Consistent with this, inhibition of Akt activity attenuated leptin- induced cell proliferation. Our results are in agreement with previous reports that PI3K-Akt transduces intracellular signals that control adult hippocampal neural progenitor cell proliferation (55,56). Overexpression of Akt increases cell proliferation, whereas expression of a dominant negative Akt inhibits cell proliferation (55,56).…”

Section: Discussionsupporting

confidence: 93%

Leptin Increases Adult Hippocampal Neurogenesis in Vivo and in Vitro

Garza

Guo

Zhang

et al. 2008

Journal of Biological Chemistry

203

161

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Leptin, an adipose-derived hormone, has been implicated in several physiological processes involving the hippocampus. However, the role of leptin in adult hippocampal neurogenesis remains unknown. Here we show that leptin regulates neurogenesis in the dentate gyrus of adult mice as well as in cultured adult hippocampal progenitor cells. Chronic administration of leptin to adult mice increased cell proliferation without significant effects on the differentiation and the survival of newly proliferated cells in the dentate gyrus. The expression of the long form leptin receptor, LepRb, was detected in hippocampal progenitor cells by reverse transcription-PCR and immunohistochemistry. Leptin treatment also increased proliferation of cultured adult hippocampal progenitor cells. Analysis of signal transduction pathways revealed that leptin stimulated phosphorylation of Akt and STAT3 but not ERK1/2. Furthermore, pretreating the cells with specific inhibitors of Akt or STAT3 attenuated leptin-induced cell proliferation in a dose-dependent manner. Taken together, our results support a role for leptin in adult hippocampal neurogenesis and suggest the involvement of the Akt and STAT3 signaling pathways in mediating the actions of leptin on neurogenesis.The dentate gyrus of the hippocampus is one of the two brain regions where adult neurogenesis persists throughout life. Adult neurogenesis is regulated by physiological and pathological events and modulated by pharmacological manipulations at any of three primary stages: cell proliferation, differentiation, and survival. Neurogenesis in the dentate gyrus has been found to be negatively influenced by stress and is suppressed in various animal models of depression (1-3). Conversely, new neuron generation in the dentate gyrus is stimulated by treatment with antidepressants (4, 5). Also, neurotrophins, growth factors, and cytokines have been shown to be capable of modulating neurogenesis of the adult dentate gyrus (6 -8).Leptin is an adipocyte-derived cytokine encoded by the obese (ob) gene. It circulates as a 16-kDa peptide and is transported into the brain via a saturable transport system (9 -11). Leptin signals in the brain by binding to the long form leptin receptor (LepRb), 2 a Type I cytokine receptor, which results in Janus kinase 2 (Jak2)-mediated phosphorylation of two tyrosine residues (Tyr 985 and Tyr 1138 ) in the cytoplasmic tail of the receptor (12). Phosphorylated Tyr 985 of LepRb recruits SH2-containing protein-tyrosine phosphatase-2, leading to activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) pathway (13,14). Phosphorylated Tyr 1138 of LepRb activates signal transducer and activator of transcription 3 (STAT3), which dimerizes and is translocated to the nucleus where it acts as a transcription factor (12). Jak2 also phosphorylates insulin receptor substrate-1 and -2, resulting in activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway (15, 16).Leptin is well known for its role in the control of food intake a...

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Section: Discussionsupporting

confidence: 93%

Leptin Increases Adult Hippocampal Neurogenesis in Vivo and in Vitro

Garza

Guo

Zhang

et al. 2008

Journal of Biological Chemistry

203

161

View full text Add to dashboard Cite

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“…Our results indicated that inhibition of these pathways attenuated NSC proliferation and neuronal differentiation induced by the drug. PI3K⅐Akt and Wnt⅐␤-catenin transduce intracellular signals that control adult hippocampal NSC proliferation and differentiation (77,78). Our results are consistent with the previous finding that valproate enhances NPC proliferation in DG via inhibiting GSK-3␤ by its phosphorylation and increasing the levels of ␤-catenin (28).…”

Section: Discussionsupporting

confidence: 92%

Ethosuximide Induces Hippocampal Neurogenesis and Reverses Cognitive Deficits in an Amyloid-β Toxin-induced Alzheimer Rat Model via the Phosphatidylinositol 3-Kinase (PI3K)/Akt/Wnt/β-Catenin Pathway

Tiwari

Seth

Agarwal

et al. 2015

Journal of Biological Chemistry

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Background: Neurogenesis, the process of generation of new neurons, is reduced in Alzheimer disease (AD). Results: Ethosuximide (ETH), an anticonvulsant drug, increased neurogenesis, reduced neurodegeneration, and reversed cognitive impairments in a rat model of AD-like phenotypes. Conclusion: ETH induces neurogenesis, thus reversing AD-like phenotypes. Significance: ETH could be used as a therapeutic molecule to enhance neurogenesis.

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“…Hypoxia induction of EPO in brain persists for up to 24 h or more [40]. In cultures of rat embryonic mesencephalic and adult subventricular zone precursor cells, EPO enhances proliferation and neuronal differentiation [41,42], providing further evidence for potential EPO activity in brain. Recently, comparisons of HIF-1α with its isoform, HIF-2α using siRNA technology suggest that HIF-2a, rather than HIF-1a, is the main regulator of EPO expression during hypoxia [43].…”

Section: Epo Production In Brainmentioning

confidence: 90%

Role of erythropoietin in the brain

Noguchi

Asavaritikrai

Teng

et al. 2007

Critical Reviews in Oncology/Hematology

206

159

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Multi-tissue erythropoietin receptor (EPO-R) expression provides for erythropoietin (EPO) activity beyond its known regulation of red blood cell production. This review highlights the role of EPO and EPO-R in brain development and neuroprotection. EPO-R brain expression includes neural progenitor cells (NPC), neurons, glial cells and endothelial cells. EPO is produced in brain in a hypoxia sensitive manner, stimulates NPC proliferation and differentiation, and neuron survival, and contributes to ischemic preconditioning. Mice lacking EPO or EPO-R exhibit increased neural cell apoptosis during development before embryonic death due to severe anemia. EPO administration provides neural protection in animal models of brain ischemia and trauma, reducing the extent of injury and damage. EPO stimulation of endothelial cells contributes to neuroprotection and is of particular importance since only low levels of EPO appear to cross the blood-brain barrier when administered at high dose intravenously. The therapeutic potential of EPO for brain ischemia/trauma and neurodegenerative diseases has shown promise in early clinical trial and awaits further validation.

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Neurogenin 1 Mediates Erythropoietin Enhanced Differentiation of Adult Neural Progenitor Cells

Cited by 53 publications

References 35 publications

Leptin Increases Adult Hippocampal Neurogenesis in Vivo and in Vitro

Leptin Increases Adult Hippocampal Neurogenesis in Vivo and in Vitro

Ethosuximide Induces Hippocampal Neurogenesis and Reverses Cognitive Deficits in an Amyloid-β Toxin-induced Alzheimer Rat Model via the Phosphatidylinositol 3-Kinase (PI3K)/Akt/Wnt/β-Catenin Pathway

Role of erythropoietin in the brain

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