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 1

Expression of WIP1 in NSCs and p53 activation during aging.

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Expression of WIP1 in NSCs and p53 activation during aging. (A) Represen...
(A) Representative image of β-gal staining of brains of Wip1-β-gal mice. LV, lateral ventricle; CC, corpus callosum; Str, stratum; SP, septum. (B) Representative photographs of colocalization analysis of Wip1-β-gal and NESTIN, MASH1, PSA-NCAM, and S100β. Note Wip1-β-gal expression in NSCs and transit-amplifying cells but not in neuroblasts. (C) Representative images of Wip1-β-gal in the SVZ regions of 2-, 4-, 7-, and 10-month-old mice. (D) Real-time PCR analysis of Wip1 mRNA in sorted LeX+CD24– SVZ cells from 2- to 3-month-old (young) and 1-year-old (old) WT mice as well as from 1-year-old Wip1-Tg mice. The gate for sorting is shown in Supplemental Figure 1D. Data are mean ± SD. (E) Analysis of EGFP signals from p21 promoter in LeX+CD24– SVZ cells obtained from 2- to 3-month-old and 1-year-old WT mice as well as from 1-year-old Wip1-Tg mice. Detailed analysis is shown in Supplemental Figure 1G. Data are mean ± SEM. (F) Quantification of percentages of DCX-positive cells after 2 days differentiation for p21-EGFP–positive and –negative cells. Data are mean ± SD. (G) Representative images of primary NSPs isolated from 2- and 9-month-old p21-EGFP reporter mice. (H) Quantification of the percentages of p21-EGFP–positive cells in primary neurospheres isolated from 2- and 9-month-old WT mice and 2-month-old Wip1 KO mice. Data are mean ± SEM. ***P < 0.005. Scale bar: 200 μm (A); 20 μm (B); 100 μm (C); 500 μm (G).