Cheng Frances Y, Fleming Jonathan T, Chiang Chin
Department of Cell and Developmental Biology, Vanderbilt University, 4114 MRB III, Nashville, TN 37232, USA.
Department of Cell and Developmental Biology, Vanderbilt University, 4114 MRB III, Nashville, TN 37232, USA.
Dev Biol. 2018 Aug 15;440(2):152-166. doi: 10.1016/j.ydbio.2018.05.015. Epub 2018 May 21.
Neuronal-glial relationships play a critical role in the maintenance of central nervous system architecture and neuronal specification. A deeper understanding of these relationships can elucidate cellular cross-talk capable of sustaining proper development of neural tissues. In the cerebellum, cerebellar granule neuron precursors (CGNPs) proliferate in response to Purkinje neuron-derived Sonic hedgehog (Shh) before ultimately exiting the cell cycle and migrating radially along Bergmann glial fibers. However, the function of Bergmann glia in CGNP proliferation remains not well defined. Interestingly, the Hh pathway is also activated in Bergmann glia, but the role of Shh signaling in these cells is unknown. In this study, we show that specific ablation of Shh signaling using the tamoxifen-inducible TNC line to eliminate Shh pathway activator Smoothened in Bergmann glia is sufficient to cause severe cerebellar hypoplasia and a significant reduction in CGNP proliferation. TNC; Smo (Smo) mice demonstrate an obvious reduction in cerebellar size within two days of ablation of Shh signaling. Mutant cerebella have severely reduced proliferation and increased differentiation of CGNPs due to a significant decrease in Shh activity and concomitant activation of Wnt signaling in Smo CGNPs, suggesting that this pathway is involved in cross-talk with the Shh pathway in regulating CGNP proliferation. In addition, Purkinje cells are ectopically located, their dendrites stunted, and the Bergmann glial network disorganized. Collectively, these data demonstrate a previously unappreciated role for Bergmann glial Shh signaling activity in the proliferation of CGNPs and proper maintenance of cerebellar architecture.
神经元与神经胶质细胞的关系在中枢神经系统结构的维持和神经元特化过程中起着关键作用。对这些关系的更深入理解能够阐明细胞间的相互作用，从而维持神经组织的正常发育。在小脑中，小脑颗粒神经元前体细胞（CGNP）会因浦肯野神经元分泌的音猬因子（Shh）而增殖，最终退出细胞周期并沿伯格曼胶质纤维进行径向迁移。然而，伯格曼胶质细胞在CGNP增殖中的功能仍未明确界定。有趣的是，Hh信号通路在伯格曼胶质细胞中也被激活，但Shh信号在这些细胞中的作用尚不清楚。在本研究中，我们发现利用他莫昔芬诱导的TNC系特异性敲除Shh信号，以消除伯格曼胶质细胞中的Shh信号通路激活剂平滑受体（Smo），足以导致严重的小脑发育不全以及CGNP增殖显著减少。TNC; Smo（Smo）小鼠在敲除Shh信号后的两天内，小脑大小明显减小。由于Shh活性显著降低以及Smo CGNP中Wnt信号的同时激活，突变小鼠的小脑CGNP增殖严重减少且分化增加，这表明该信号通路在调节CGNP增殖过程中与Shh信号通路存在相互作用。此外，浦肯野细胞位置异常，其树突发育不良，伯格曼胶质细胞网络紊乱。总体而言，这些数据表明伯格曼胶质细胞的Shh信号活性在CGNP增殖和小脑结构的正常维持中具有此前未被认识到的作用。
