Research Center for Stem Cell Engineering, National Institute of Advanced Industrial Science and Technology, Central 4, 1-1-4 Higashi, Tsukuba, 305-8562, Japan.
FASEB J. 2011 Oct;25(10):3570-82. doi: 10.1096/fj.11-184697. Epub 2011 Jul 11.
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.
哺乳动物的大脑中含有神经干细胞（NSCs），这些细胞能够在成年后持续产生新的神经元。然而，随着年龄的增长，NSC 的功能和/或数量会下降。成年海马体神经发生的独特之处在于，星形胶质细胞分泌的 Wnt3 以旁分泌的方式促进 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年神经发生的损伤。与年龄相关的 Wnt3 水平下降会影响靶基因（如 NeuroD1 和逆转录转座子 L1）的调节，以及位于 L1 基因座附近的 Dcx 的表达。有趣的是，随着年龄的增长，外源性 Wnt3 水平和靶基因的细胞内表达下降是可以逆转的。研究发现，运动显著增加了 Wnt3 的从头表达，从而挽救了老年动物受损的神经发生。此外，NeuroD1、L1 和 Dcx 附近的 L1 基因座的染色质状态相对于 Wnt3 水平会发生与年龄或刺激相关的变化。这些结果表明，旁分泌因子的调节在海马体衰老和神经发生中起着关键作用。
