title: 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.forename: Yunhua
authors.initials: Y
authors.lastname: Zhu
authors.forename: Oleg N
authors.initials: ON
authors.lastname: Demidov
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Goh
authors.forename: David M
authors.initials: DM
authors.lastname: Virshup
authors.forename: David P
authors.initials: DP
authors.lastname: Lane
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Bulavin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D053687:Adult Stem Cells / Q000378:metabolism / Q000473:pathology; D000375:Aging / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D055696:Olfactory Perception / Q000502:physiology; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C405061:Dkk3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D016159:Tumor Suppressor Protein p53; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C