Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Aging

Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging

  • Text
  • PDF
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

×

Figure 2

Wip1-Tg expression improves new neuron formation and NSC activity in aged mice.

Options: View larger image (or click on image) Download as PowerPoint

Wip1-Tg expression improves new neuron formation and NSC activity in ag...
(A) Quantification of BrdU-positive cells in OBs of young (3- to 4-month-old) and old (16- to 18-month-old) mice of different genotypes. Data are mean ± SEM. (B) Quantification of NEUN-positive cells over total newly formed cells, and a representative photograph of EdU/NEUN colabeling 1 month after EdU injection in aged Wip1-Tg mice. Arrowheads indicate examples of EdU-positive nuclei that colocalize with NEUN. A arrow indicates an EdU-positive, NEUN-negative cell. Data are mean ± SEM. (C) Quantification of the proportion of calretinin-positive newborn neurons (calretinin+EdU+ cells) over total EdU-positive cells (EdU+ cells), and a representative photograph of EdU/calretinin colabeling 1 month after EdU injection in aged Wip1-Tg mice. Data are mean ± SEM. (D) Representative image of EdU/NESTIN colabeling from aged Wip1-Tg mice and quantification of LR-BrdU–positive cells per SVZ section in WT, Wip1-Tg, p16Ink4a KO, and Wip1-Tg /p16Ink4a KO mice. Additional analysis of EdU-labeled cells is provided in Supplemental Figure 3, F and G. Data are mean ± SEM. (E) Quantification of short-term incorporation of BrdU, a proliferation marker of NPCs. Data are mean ± SEM. (F) Quantification of DCX-positive cells in young and aged WT and Wip1-Tg SVZs. Representative photographs of DCX staining in the SVZ areas of young and aged WT and aged Wip1-Tg mice, and quantification of DCX-positive area in the SVZ. Data are mean ± SD. *P < 0.05; ***P < 0.005. Scale bar: 40 μm (B); 30 μm (C); 20 μm (D); 200 μm (F).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts