Reduction in paracrine Wnt3 factors during aging causes impaired adult neurogenesis
Reduction in paracrine Wnt3 factors during aging causes impaired adult neurogenesis
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DOI：
10.1096/fj.11-184697
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发表时间：
2011-10-01
期刊：
影响因子：
4.8
通讯作者：
Kuwabara, Tomoko
中科院分区：
文献类型：
--
作者：
Okamoto, Masahiro;Inoue, Koshiro;Kuwabara, Tomoko
哺乳动物的大脑中含有神经干细胞（NSCs），能够在成年期持续发生神经。然而，随着年龄的增长，NSC的功能和/或数量下降。成人海马神经发生的独特之处在于分泌Wnt3的星形胶质细胞以旁分泌方式促进NSC分化。在这里，我们发现Wnt3蛋白的水平和分泌Wnt3的星形胶质细胞的数量都会影响衰老过程中成人神经发生的损伤。年龄相关的Wnt3水平降低会影响靶基因的调控，如NeuroD1和反转录转座子L1，以及位于L1位点附近的Dcx的表达。有趣的是，随着年龄的增长，外源性Wnt3水平和靶基因细胞内表达的下降是可逆的。研究发现，运动可以显著增加Wnt3的新生表达，从而挽救老龄动物受损的神经发生。此外，神经d1、L1和Dcx附近L1位点的染色质状态以年龄或刺激相关的方式相对于Wnt3水平发生变化。这些结果表明，旁分泌因子的调节在海马衰老和神经发生中起着关键作用。-Okamoto， M., Inoue， K., Iwamura， H., Terashima， K., Soya， H., Asashima， M., Kuwabara， T.衰老过程中旁分泌Wnt3因子的减少导致成人神经发生受损。中国生物医学工程学报，2011,32(2):444 - 444。www.fasebj.org
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.-Okamoto, M., Inoue, K., Iwamura, H., Terashima, K., Soya, H., Asashima, M., Kuwabara, T. Reduction in paracrine Wnt3 factors during aging causes impaired adult neurogenesis. FASEB J. 25, 3570 - 3582 (2011). www.fasebj.org