| RRC ID |
35756
|
| 著者 |
Zhu Y, Demidov ON, Goh AM, Virshup DM, Lane DP, Bulavin DV.
|
| タイトル |
Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging.
|
| ジャーナル |
J Clin Invest
|
| Abstract |
The number of newly formed neurons declines rapidly during aging, and this decrease in neurogenesis is associated with decreased function of neural stem/progenitor cells (NPCs). Here, we determined that a WIP1-dependent pathway regulates NPC differentiation and contributes to the age-associated decline of neurogenesis. Specifically, we found that WIP1 is expressed in NPCs of the mouse subventricular zone (SVZ) and aged animals with genetically enhanced WIP1 expression exhibited higher NPC numbers and neuronal differentiation compared with aged WT animals. Additionally, augmenting WIP1 expression in aged animals markedly improved neuron formation and rescued a functional defect in fine odor discrimination in aged mice. We identified the WNT signaling pathway inhibitor DKK3 as a key downstream target of WIP1 and found that expression of DKK3 in the SVZ is restricted to NPCs. Using murine reporter strains, we determined that DKK3 inhibits neuroblast formation by suppressing WNT signaling and Dkk3 deletion or pharmacological activation of the WNT pathway improved neuron formation and olfactory function in aged mice. We propose that WIP1 controls DKK3-dependent inhibition of neuronal differentiation during aging and suggest that regulating WIP1 levels could prevent certain aspects of functional decline of the aging brain.
|
| 巻・号 |
124(7)
|
| ページ |
3263-73
|
| 公開日 |
2014-7-1
|
| DOI |
10.1172/JCI73015
|
| PII |
73015
|
| PMID |
24911145
|
| PMC |
PMC4071391
|
| MeSH |
Adaptor Proteins, Signal Transducing
Adult Stem Cells / metabolism
Adult Stem Cells / pathology
Aging / metabolism*
Aging / pathology*
Animals
Brain / metabolism
Brain / pathology
Cell Differentiation
Intercellular Signaling Peptides and Proteins / deficiency
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism
Mice
Mice, Knockout
Mice, Transgenic
Neural Stem Cells / metabolism
Neural Stem Cells / pathology
Neurogenesis / genetics
Neurogenesis / physiology*
Olfactory Perception / physiology
Phosphoprotein Phosphatases / genetics
Phosphoprotein Phosphatases / metabolism*
Protein Phosphatase 2C
Tumor Suppressor Protein p53 / metabolism
Wnt Signaling Pathway*
|
| IF |
11.864
|
| 引用数 |
39
|
|
WOS 分野
|
MEDICINE, RESEARCH & EXPERIMENTAL
|
| リソース情報 |
| 実験動物マウス |
RBRC02847 |
