Inducible and conditional deletion of extracellular signal-regulated kinase 5 disrupts adult hippocampal neurogenesis.
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.
Graduate Program in Molecular and Cellular Biology, Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195, USA.
Yung-Wei
YW
Pan
Junhui
J
Zou
Wenbin
W
Wang
Hiroyuki
H
Sakagami
Michael G
MG
Garelick
Glen
G
Abel
Chay T
CT
Kuo
Daniel R
DR
Storm
Zhengui
Z
Xia
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018891:Dentate Gyrus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D048671:MAP Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009414:Nerve Growth Factors / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D055495:Neurogenesis; D034622:RNA Interference; D013629:Tamoxifen / Q000494:pharmacology
D018931:Antineoplastic Agents, Hormonal; D051792:Basic Helix-Loop-Helix Proteins; D008164:Luminescent Proteins; D048671:MAP Kinase Kinase 5; D048054:Mitogen-Activated Protein Kinase 7; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D013629:Tamoxifen; C102938:Neurog2 protein, mouse