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Inducible and conditional deletion of extracellular signal-regulated kinase 5 disrupts adult hippocampal neurogenesis.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2012 Jul 06; Vol. 287 (28), pp. 23306-17. Date of Electronic Publication: 2012 May 29. - Publication Year :
- 2012
-
Abstract
- Recent studies have led to the exciting idea that adult-born neurons in the dentate gyrus of the hippocampus may play a role in hippocampus-dependent memory formation. However, signaling mechanisms that regulate adult hippocampal neurogenesis are not well defined. Here we report that extracellular signal-regulated kinase 5 (ERK5), a member of the mitogen-activated protein kinase family, is selectively expressed in the neurogenic regions of the adult mouse brain. We present evidence that shRNA suppression of ERK5 in adult hippocampal neural stem/progenitor cells (aNPCs) reduces the number of neurons while increasing the number of cells expressing markers for stem/progenitor cells or proliferation. Furthermore, shERK5 attenuates both transcription and neuronal differentiation mediated by Neurogenin 2, a transcription factor expressed in adult hippocampal neural progenitor cells. By contrast, ectopic activation of endogenous ERK5 signaling via expression of constitutive active MEK5, an upstream activating kinase for ERK5, promotes neurogenesis in cultured aNPCs and in the dentate gyrus of the mouse brain. Moreover, neurotrophins including NT3 activate ERK5 and stimulate neuronal differentiation in aNPCs in an ERK5-dependent manner. Finally, inducible and conditional deletion of ERK5 specifically in the neurogenic regions of the adult mouse brain delays the normal progression of neuronal differentiation and attenuates adult neurogenesis in vivo. These data suggest ERK5 signaling as a critical regulator of adult hippocampal neurogenesis.
- Subjects :
- Animals
Antineoplastic Agents, Hormonal pharmacology
Basic Helix-Loop-Helix Transcription Factors genetics
Basic Helix-Loop-Helix Transcription Factors metabolism
Blotting, Western
Cell Differentiation drug effects
Cell Proliferation drug effects
Cells, Cultured
Dentate Gyrus cytology
Dentate Gyrus growth & development
Dentate Gyrus metabolism
Hippocampus cytology
Hippocampus growth & development
Luminescent Proteins genetics
Luminescent Proteins metabolism
MAP Kinase Kinase 5 genetics
MAP Kinase Kinase 5 metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Microscopy, Confocal
Mitogen-Activated Protein Kinase 7 genetics
NIH 3T3 Cells
Nerve Growth Factors pharmacology
Nerve Tissue Proteins genetics
Nerve Tissue Proteins metabolism
Neural Stem Cells cytology
Neural Stem Cells drug effects
RNA Interference
Tamoxifen pharmacology
Hippocampus metabolism
Mitogen-Activated Protein Kinase 7 metabolism
Neural Stem Cells metabolism
Neurogenesis
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 287
- Issue :
- 28
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22645146
- Full Text :
- https://doi.org/10.1074/jbc.M112.344762