RRC ID 35756
Author Zhu Y, Demidov ON, Goh AM, Virshup DM, Lane DP, Bulavin DV.
Title Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging.
Journal J Clin Invest
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.
Volume 124(7)
Pages 3263-73
Published 2014-7-1
DOI 10.1172/JCI73015
PII 73015
PMID 24911145
PMC PMC4071391
MeSH Adaptor Proteins, Signal Transducing Adult Stem Cells / metabolism Adult Stem Cells / pathology Aging / metabolism* Aging / pathology* Animals Brain / metabolism Brain / pathology Cell Differentiation Intercellular Signaling Peptides and Proteins / deficiency Intercellular Signaling Peptides and Proteins / genetics Intercellular Signaling Peptides and Proteins / metabolism Mice Mice, Knockout Mice, Transgenic Neural Stem Cells / metabolism Neural Stem Cells / pathology Neurogenesis / genetics Neurogenesis / physiology* Olfactory Perception / physiology Phosphoprotein Phosphatases / genetics Phosphoprotein Phosphatases / metabolism* Protein Phosphatase 2C Tumor Suppressor Protein p53 / metabolism Wnt Signaling Pathway*
IF 11.864
Times Cited 39
Mice RBRC02847