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 5

Expression and functional analysis of DKK3.

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Expression and functional analysis of DKK3. (A) Representative images of...
(A) Representative images of EGFP (green) expression in the brains of Dkk3-EGFP-Tg mice. An overview of the lateral ventricle area is shown. These Dkk3-EGFP–positive cells are largely positive for SOX2, partially positive for MASH1 (highlighted with white arrowheads), and negative for S100β and Tuj1. (B) Quantification of relative numbers of NSPs formed from total Dkk3-EGFP–positive and –negative cells SVZ cells. Detailed analysis of NSP formation is presented in Supplemental Figure 4E. Data are mean ± SD. (C) Representative images of Axin2-β-gal staining in young (2-month-old) and old (2-year-old) forebrains. Enlarged images are shown below. (D) Representative images for Axin2-β-gal activity in SVZs of 4-month-old WT and Wip1 KO mice. (E) Representative images for Axin2-β-gal activity in SVZs of 1-year-old WT and Wip1-Tg mice. (F) Representative images of Axin2-β-gal staining of cultured NPCs after 2 days treatment with vehicle, WNT3a, WNT3a plus DKK3, or WNT3a plus DKK1. Quantification of Axin2-β-gal–positive cells in different groups. Data are mean ± SEM. (G) Analysis of neuroblasts formation 2 days after differentiation of NPCs on coverslips in the presence of WNT3a or WNT3a and DKK3. Representative images of DCX staining (arrows indicate neuroblasts). Quantification of the effects of WNT3 and DKK3 on formation of DCX-positive neuroblasts. Data are mean ± SD. *P < 0.05; ***P < 0.005. Scale bar: 100 μm (A, top left, and G); 20 μm (A, top right, middle, and bottom); 1 mm (C, top row); 50 μm (C, bottom row, and D–F).