Department of Chemical and Biomolecular Engineering, University of California Berkeley, Berkeley, California, USA.
Nat Neurosci. 2012 Oct;15(10):1399-406. doi: 10.1038/nn.3212. Epub 2012 Sep 16.
Neurogenesis in the adult hippocampus involves activation of quiescent neural stem cells (NSCs) to yield transiently amplifying NSCs, progenitors, and, ultimately, neurons that affect learning and memory. This process is tightly controlled by microenvironmental cues, although a few endogenous factors are known to regulate neuronal differentiation. Astrocytes have been implicated, but their role in juxtacrine (that is, cell-cell contact dependent) signaling in NSC niches has not been investigated. We found that ephrin-B2 presented from rodent hippocampal astrocytes regulated neurogenesis in vivo. Furthermore, clonal analysis in NSC fate-mapping studies revealed a previously unknown role for ephrin-B2 in instructing neuronal differentiation. In addition, ephrin-B2 signaling, transduced by EphB4 receptors on NSCs, activated β-catenin in vitro and in vivo independently of Wnt signaling and upregulated proneural transcription factors. Ephrin-B2(+) astrocytes therefore promote neuronal differentiation of adult NSCs through juxtacrine signaling, findings that advance our understanding of adult neurogenesis and may have future regenerative medicine implications.
成年海马体中的神经发生涉及静息神经干细胞 (NSC) 的激活，以产生短暂扩增的 NSCs、祖细胞，最终产生影响学习和记忆的神经元。这个过程受到微环境线索的严格控制，尽管有一些内源性因素被认为可以调节神经元分化。星形胶质细胞已经被牵涉进来，但它们在 NSC 生态位中的旁分泌（即细胞-细胞接触依赖性）信号中的作用尚未被研究。我们发现，来自啮齿动物海马星形胶质细胞的 Ephrin-B2 调节体内的神经发生。此外，在 NSC 命运映射研究中的克隆分析揭示了 Ephrin-B2 在指导神经元分化方面的先前未知作用。此外，EphB4 受体转导的 Ephrin-B2 信号在体外和体内独立于 Wnt 信号激活 β-catenin，并上调原神经转录因子。因此，Ephrin-B2(+)星形胶质细胞通过旁分泌信号促进成年 NSCs 的神经元分化，这一发现推进了我们对成年神经发生的理解，并且可能对未来的再生医学具有重要意义。
