Mature Purkinje Cells Require the Retinoic Acid-Related Orphan Receptor-α (ROR α) to Maintain Climbing Fiber Mono-Innervation and Other Adult Characteristics
Mature Purkinje Cells Require the Retinoic Acid-Related Orphan Receptor-α (ROR α) to Maintain Climbing Fiber Mono-Innervation and Other Adult Characteristics
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DOI：
10.1523/jneurosci.2977-12.2013
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发表时间：
2013-05-29
影响因子：
5.3
通讯作者：
Dusart, Isabelle
中科院分区：
文献类型：
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作者：
Chen, Xiao Ru;Heck, Nicolas;Dusart, Isabelle
神经元发育成熟是一个受转录因子调控的多步骤过程。转录因子ROR α（视黄酸相关孤儿受体α）是早期浦肯野细胞（PC）成熟所必需的，但也在整个成年期表达。为了鉴定ROR α在成熟PC中的作用，我们在体内使用Cre-lox小鼠遗传工具，在出生后第10 - 21天之间从PC中特异性地删除它。到14日龄，突变体和对照PC之间的差异是不可检测的：都是单神经支配的攀爬纤维（CF）延伸沿着他们发育良好的树突与多刺的小枝。到第4周，突变小鼠出现共济失调，一些PC死亡，剩余的PC索马和树突萎缩，多刺小枝几乎完全消失。存活的ROR α-缺失PC的神经支配模式是异常的，具有一些不成熟的特征。值得注意的是，多功能CF神经支配重建这些成熟的PC，同时搬迁CF接触PC索马和他们的茎树突。CF接触的这种形态学修饰甚至可以在更晚的时候诱导，使用慢病毒介导的从成人PC中消耗rora。这些数据表明，出生后晚期ROR α细胞表达自主调节PC树突复杂性的维持，以及PC的CF神经支配状态（树突与躯体接触，以及单神经支配与多神经支配）。因此，成年神经元的分化状态是在转录因子的控制下;如果没有转录因子，成年神经元将失去其成熟特征，并获得早期发育阶段的一些特征。
Neuronal maturation during development is a multistep process regulated by transcription factors. The transcription factor ROR alpha (retinoic acid-related orphan receptor alpha) is necessary for early Purkinje cell (PC) maturation but is also expressed throughout adulthood. To identify the role of ROR alpha in mature PCs, we used Cre-lox mouse genetic tools in vivo that delete it specifically from PCs between postnatal days 10 -21. Up to 14 d of age, differences between mutant and control PCs were not detectable: both were mono-innervated by climbing fibers (CFs) extending along their well-developed dendrites with spiny branchlets. By week 4, mutant mice were ataxic, some PCs had died, and remaining PC soma and dendrites were atrophic, with almost complete disappearance of spiny branchlets. The innervation pattern of surviving ROR alpha -deleted PCs was abnormal with several immature characteristics. Notably, multiple functional CF innervation was reestablished on these mature PCs, simultaneously with the relocation of CF contacts to the PC soma and their stem dendrite. This morphological modification of CF contacts could be induced even later, using lentivirus-mediated depletion of rora from adult PCs. These data show that the late postnatal expression of ROR alpha cell-autonomously regulates the maintenance of PC dendritic complexity, and the CF innervation status of the PC (dendritic vs somatic contacts, and mono-innervation vs multi-innervation). Thus, the differentiation state of adult neurons is under the control of transcription factors; and in their absence, adult neurons lose their mature characteristics and acquire some characteristics of an earlier developmental stage.