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Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging
Yunhua Zhu, … , David P. Lane, Dmitry V. Bulavin
Yunhua Zhu, … , David P. Lane, Dmitry V. Bulavin
Published June 9, 2014
Citation Information: J Clin Invest. 2014;124(7):3263-3273. https://doi.org/10.1172/JCI73015.
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Research Article Aging

Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging

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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.

Authors

Yunhua Zhu, Oleg N. Demidov, Amanda M. Goh, David M. Virshup, David P. Lane, Dmitry V. Bulavin

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Figure 3

Wip1-Tg mice exhibit improved fine odor discrimination.

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Wip1-Tg mice exhibit improved fine odor discrimination.
(A) The design ...
(A) The design of the fine odor discrimination test. Mice were deprived of water for 2 days and trained to identify distilled water. The distilled water was coupled with an odor mixture of mango and almond; however, mango was the main component. In another dish, bitter water was coupled with a mixture in which almond was the main component. Different proportions of the odors were used for the performance test. (B) Test performance of young (3- to 4-month-old) WT and Wip1-Tg mice shows no differences in fine odor discrimination. Data are mean ± SEM. (C) Test performance of old (16- to 18-month-old) WT and Wip1-Tg mice shows a significantly better fine odor discrimination of Wip1-Tg. Data are mean ± SEM. (D) Representative images and quantification of EdU labeling (2-hour pulse) of neural progenitors. Mice were treated with AraC for 1 month (described in Methods). Insets show colabeling of EdU, DCX, and DAPI. Note a decrease in both EdU- and DCX-positive cells in AraC-treated mice. Data are mean ± SEM. (E) Representative images and quantification of EdU-positive cells 1 month after EdU labeling in control mice and in mice treated with AraC. AraC treatment started right before EdU injection. Data are mean ± SEM. (F) Test performance of AraC-treated and control 1-year-old Wip1-Tg mice. Note that there is a significant reduction in performance after AraC treatment. Data are mean ± SEM. *P < 0.05; ***P < 0.005. Scale bar: 200 μm (D and E); 100 μm (D, inset); 40 μm (E, inset).

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