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

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 6

Characterization of adult neurogenesis in Dkk3 KO mice.

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Characterization of adult neurogenesis in Dkk3 KO mice. (A) Quantificati...
(A) Quantification of long-term EdU-retaining cells in SVZs of 6-month-old WT and Dkk3 KO mice. Data are mean ± SEM. (B) Quantification of labeled cells after a 2-hour BrdU pulse of same set of mice as in A. Data are mean ± SEM. (C) Analysis of DCX-positive cells in SVZs of 6-month-old WT and Dkk3 KO mice. Data are mean ± SEM. (D) Photographs showing DCX-positive cells in the OBs of WT and Dkk3 KO mice. (E) Quantification of EdU-positive cells that have integrated in the OBs 1 month after EdU labeling. Data are mean ± SEM. (F) Quantification of NEUN-positive cells over total EdU-positive cells in WT and Dkk3 KO mice. Data are mean ± SEM. (G) Quantification of the proportion of NEUN-negative newborn cells over total EdU-positive cells in WT and Dkk3 KO mice. Data are mean ± SEM. (H) Test performance of WT and Dkk3 KO mice at 3 to 5 months of age. Data are mean ± SEM. (I) Quantification of new cell (EdU+) formation in 14-month-old mice after treatment with a GSK3 inhibitor (SB216763). Data are mean ± SEM. (J) Test performance of WT mice at 8 months of age 4 weeks after injection of vehicle or a GSK3 inhibitor (SB216763). Data are mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.005. Scale bar: 200 μm (C); 100 μm (C, inset, and D).