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Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging.

Publication ,  Journal Article
Zhu, Y; Demidov, ON; Goh, AM; Virshup, DM; Lane, DP; Bulavin, DV
Published in: J Clin Invest
July 2014

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.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

July 2014

Volume

124

Issue

7

Start / End Page

3263 / 3273

Location

United States

Related Subject Headings

  • Wnt Signaling Pathway
  • Tumor Suppressor Protein p53
  • Protein Phosphatase 2C
  • Phosphoprotein Phosphatases
  • Olfactory Perception
  • Neurogenesis
  • Neural Stem Cells
  • Mice, Transgenic
  • Mice, Knockout
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Zhu, Y., Demidov, O. N., Goh, A. M., Virshup, D. M., Lane, D. P., & Bulavin, D. V. (2014). Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging. J Clin Invest, 124(7), 3263–3273. https://doi.org/10.1172/JCI73015
Zhu, Yunhua, Oleg N. Demidov, Amanda M. Goh, David M. Virshup, David P. Lane, and Dmitry V. Bulavin. “Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging.J Clin Invest 124, no. 7 (July 2014): 3263–73. https://doi.org/10.1172/JCI73015.
Zhu Y, Demidov ON, Goh AM, Virshup DM, Lane DP, Bulavin DV. Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging. J Clin Invest. 2014 Jul;124(7):3263–73.
Zhu, Yunhua, et al. “Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging.J Clin Invest, vol. 124, no. 7, July 2014, pp. 3263–73. Pubmed, doi:10.1172/JCI73015.
Zhu Y, Demidov ON, Goh AM, Virshup DM, Lane DP, Bulavin DV. Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging. J Clin Invest. 2014 Jul;124(7):3263–3273.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

July 2014

Volume

124

Issue

7

Start / End Page

3263 / 3273

Location

United States

Related Subject Headings

  • Wnt Signaling Pathway
  • Tumor Suppressor Protein p53
  • Protein Phosphatase 2C
  • Phosphoprotein Phosphatases
  • Olfactory Perception
  • Neurogenesis
  • Neural Stem Cells
  • Mice, Transgenic
  • Mice, Knockout
  • Mice