Inducible and Conditional Deletion of Extracellular Signal-regulated Kinase 5 Disrupts Adult Hippocampal Neurogenesis

Pan, Yii‐Wen; Zou, Jie; Wang, Wenbin; Sakagami, Hiroyuki; Garelick, Michael G.; Abel, Glen M.; Kuo, Chay T.; Storm, Daniel R.; Xia, Zhengui

doi:10.1074/jbc.m112.344762

Cited by 42 publications

(68 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To determine the relative contribution of NSPCs to VEGF in the neurogenic niche, we created an in vivo, NSPC-specific, inducible VEGF knockdown model by crossing VEGF fl mice (23) with NestinCreER T2 mice (24). When exposed to tamoxifen (TAM), NestinCreER T2 drives high levels of recombination in NSPCs in the adult SGZ, with high specificity and low toxicity (24)(25)(26). Crossing the NestinCreER T2 mouse with an R26-enhanced YFP reporter mouse (27) Fig.…”

Section: Resultsmentioning

confidence: 99%

Adult hippocampal neural stem and progenitor cells regulate the neurogenic niche by secreting VEGF

Kirby

Kuwahara

Messer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

131

100

View full text Add to dashboard Cite

The adult hippocampus hosts a population of neural stem and progenitor cells (NSPCs) that proliferates throughout the mammalian life span. To date, the new neurons derived from NSPCs have been the primary measure of their functional relevance. However, recent studies show that undifferentiated cells may shape their environment through secreted growth factors. Whether endogenous adult NSPCs secrete functionally relevant growth factors remains unclear. We show that adult hippocampal NSPCs secrete surprisingly large quantities of the essential growth factor VEGF in vitro and in vivo. This self-derived VEGF is functionally relevant for maintaining the neurogenic niche as inducible, NSPC-specific loss of VEGF results in impaired stem cell maintenance despite the presence of VEGF produced from other niche cell types. These findings reveal adult hippocampal NSPCs as an unanticipated source of an essential growth factor and imply an exciting functional role for adult brain NSPCs as secretory cells.adult neurogenesis | vascular endothelial growth factor | stem cell | hippocampus | neural precursor

show abstract

Section: Resultsmentioning

confidence: 99%

Adult hippocampal neural stem and progenitor cells regulate the neurogenic niche by secreting VEGF

Kirby

Kuwahara

Messer

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

131

100

View full text Add to dashboard Cite

show abstract

“…Retrovirus Construction, Preparation, and Infection-The construction, preparation, and infection procedures of the ERK5 shRNA (shERK5) and control nonspecific shRNA (shNS) retroviruses have been previously described (19,26).…”

Section: Methodsmentioning

confidence: 99%

Extracellular Signal-regulated Kinase 5 (ERK5) Mediates Prolactin-stimulated Adult Neurogenesis in the Subventricular Zone and Olfactory Bulb

Wang

Pan

Wietecha

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background: Signaling mechanisms underlying prolactin-induced adult neurogenesis are unknown. Results: Prolactin activates ERK5 in SVZ; suppression of ERK5 expression in vitro and erk5 deletion in vivo attenuates prolactininduced adult neurogenesis. Conclusion: ERK5 is an important mediator in prolactin-stimulated adult neurogenesis. Significance: Elucidation of signaling pathways underlying prolactin-induced adult neurogenesis is critical for understanding the fundamental role of adult neurogenesis in reproductive functions and behaviors.

show abstract

“…Like most kinases including MAPK members, ERK5 function is assumed to be driven by its kinase activity. ERK5 deletion is embryonic lethal in mice and a variety of tissue-or development-stage restricted KOs have shown clear phenotypes, suggesting that the catalytic function and/or an aspect of the nonkinase domain(s) have key roles in development and mature organ function (14)(15)(16)(17)(18). The availability of the first ERK5 inhibitor XMD8-92 enabled the study of phenotypes resulting from direct kinase inhibition (19,20).…”

mentioning

confidence: 99%

ERK5 kinase activity is dispensable for cellular immune response and proliferation

Lin¹,

Amantea²,

Nomanbhoy³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

View full text Add to dashboard Cite

Unlike other members of the MAPK family, ERK5 contains a large C-terminal domain with transcriptional activation capability in addition to an N-terminal canonical kinase domain. Genetic deletion of ERK5 is embryonic lethal, and tissue-restricted deletions have profound effects on erythroid development, cardiac function, and neurogenesis. In addition, depletion of ERK5 is antiinflammatory and antitumorigenic. Small molecule inhibition of ERK5 has been shown to have promising activity in cell and animal models of inflammation and oncology. Here we report the synthesis and biological characterization of potent, selective ERK5 inhibitors. In contrast to both genetic depletion/deletion of ERK5 and inhibition with previously reported compounds, inhibition of the kinase with the most selective of the new inhibitors had no antiinflammatory or antiproliferative activity. The source of efficacy in previously reported ERK5 inhibitors is shown to be off-target activity on bromodomains, conserved protein modules involved in recognition of acetyl-lysine residues during transcriptional processes. It is likely that phenotypes reported from genetic deletion or depletion of ERK5 arise from removal of a noncatalytic function of ERK5. The newly reported inhibitors should be useful in determining which of the many reported phenotypes are due to kinase activity and delineate which can be pharmacologically targeted.) is a member of the mitogen-activated protein kinase (MAPK) family, which includes ERK1/2, JNK1/2/3, and p38α/β/δ/γ (1). However, unlike the other MAPK members, ERK5 contains a unique 400-amino-acid C-terminal domain in addition to the kinase domain. Through the MAPK signaling cascade, mitogenactivated protein kinase kinase 5 (MEK5) activates ERK5 by phosphorylating the TEY motif in the N-terminal activation loop (2). This event unlocks the N-and C-terminal halves, allowing ERK5 to auto-phosphorylate multiple sites in its C-terminal region, which can then regulate nuclear shuttling and gene transcription (3, 4). Noncanonical pathways (including cyclin-dependent kinases during mitosis and ERK1/2 during growth factor stimulation) also exist for phosphorylation of sites in the ERK5 tail (5-7). Although ERK5 has been demonstrated to directly phosphorylate transcription factors (8-10), the noncatalytic C-terminal tail of ERK5 can also interact with transcription factors and influence gene expression (4,11,12).ERK5 can be activated in response to a range of mitogenic stimuli [e.g., growth factors, G protein-coupled receptor (GPCR) agonists, cytokines] and cellular stresses (e.g., hypoxia, shear stress) (13). Like most kinases including MAPK members, ERK5 function is assumed to be driven by its kinase activity. ERK5 deletion is embryonic lethal in mice and a variety of tissue-or development-stage restricted KOs have shown clear phenotypes, suggesting that the catalytic function and/or an aspect of the nonkinase domain(s) have key roles in development and mature organ function (14-18). The availability of the first ERK5 inhibitor ...

show abstract

Inducible and Conditional Deletion of Extracellular Signal-regulated Kinase 5 Disrupts Adult Hippocampal Neurogenesis

Cited by 42 publications

References 67 publications

Adult hippocampal neural stem and progenitor cells regulate the neurogenic niche by secreting VEGF

Adult hippocampal neural stem and progenitor cells regulate the neurogenic niche by secreting VEGF

Extracellular Signal-regulated Kinase 5 (ERK5) Mediates Prolactin-stimulated Adult Neurogenesis in the Subventricular Zone and Olfactory Bulb

ERK5 kinase activity is dispensable for cellular immune response and proliferation

Contact Info

Product

Resources

About