title: Reduction in paracrine Wnt3 factors during aging causes impaired adult neurogenesis.
abstract: The mammalian brain contains neural stem cells (NSCs) that enable continued neurogenesis throughout adulthood. However, NSC function and/or numbers decline with increasing age. Adult hippocampal neurogenesis is unique in that astrocytes secreting Wnt3 promote NSC differentiation in a paracrine manner. Here, we show that both the levels of Wnt3 protein and the number of Wnt3-secreting astrocytes influence the impairment of adult neurogenesis during aging. The age-associated reduction in Wnt3 levels affects the regulation of target genes, such as NeuroD1 and retrotransposon L1, as well as the expression of Dcx, which is located adjacent to the L1 loci. Interestingly, the decline in the extrinsic Wnt3 levels and in the intracellular expression of the target genes with aging was reversible. Exercise was found to significantly increase de novo expression of Wnt3 and thereby rescue impaired neurogenesis in aged animals. Furthermore, the chromatin state of NeuroD1, L1, and the L1 loci near Dcx changed relative to Wnt3 levels in an age- or stimulus-associated manner. These results suggest that the regulation of paracrine factors plays a critical role in hippocampal aging and neurogenesis.
authors: Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology, Central 4, 1-1-4 Higashi, Tsukuba, 305-8562, Japan.
authors: Masahiro
authors: M
authors: Okamoto
authors: Koshiro
authors: K
authors: Inoue
authors: Hiroki
authors: H
authors: Iwamura
authors: Kazuyuki
authors: K
authors: Terashima
authors: Hideaki
authors: H
authors: Soya
authors: Makoto
authors: M
authors: Asashima
authors: Tomoko
authors: T
authors: Kuwabara
mesh_terms: D000375:Aging; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002843:Chromatin; D000089662:Doublecortin Protein; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006624:Hippocampus; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000502:physiology*; D010805:Physical Conditioning, Animal; D015398:Signal Transduction; D060508:Wnt3 Protein / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D000089662:Doublecortin Protein; D060508:Wnt3 Protein; C000714847:Dcx protein, mouse; C501008:Neurod1 protein, mouse; C555508:Wnt3 protein, mouse