Plasticity of the developmentally arrested staggerer cerebellum in response to exogenous RORα
Plasticity of the developmentally arrested staggerer cerebellum in response to exogenous RORα
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DOI：
10.1007/s00429-015-1077-9
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发表时间：
2016-07-01
影响因子：
3.1
通讯作者：
Hirai, Hirokazu
中科院分区：
文献类型：
--
作者：
Iizuka, Akira;Matsuzaki, Yasunori;Hirai, Hirokazu
类视黄醇相关孤儿受体α (ROR α)是控制出生后小脑发育的关键主转录因子。ROR α缺失小鼠的小脑在3周龄后具有持久的外颗粒层（EGL），基本的浦肯野细胞（PC）树突，未成熟的平行纤维(PF)-PC突触数量严重减少，以及多种攀爬纤维（CF）控制PC，而这些特征在野生型小鼠中消失。在功能上，代谢谷氨酸受体（mGluR）介导的信号在pc中完全被废除。在这里，我们研究了这些缺陷是否可以通过慢病毒提供ROR α基因给3周龄的ROR α缺陷纯合子错叉（sg/sg）小鼠的PCs来纠正。在sg/sg PCs中ROR α的表达显著增加了PF-PC突触、PC树突小枝上的棘和内部颗粒细胞的数量，并伴有EGL的消退，表明EGL的增殖增强，有丝分裂后的后代向内部颗粒层迁移，增加了pf和PC树突之间的突触发生。然而，初级树突茎仅轻微延长，mGluR信号和多余CF突触的丢失在sg/sg PCs中仍未恢复。这些结果表明，3周龄sg/sg小鼠小脑中保留了外部颗粒细胞对ROR α的有丝分裂和迁移潜能。此外，sg/sg PCs与PFs萌发出棘并形成突触。然而，在3周龄时，sg/sg PCs中初级树突茎的延长、mGluR信号的建立和CF突触的去除都有所消退。
Retinoid-related orphan receptor alpha (ROR alpha) is a critical master transcription factor that governs postnatal cerebellar development. An ROR alpha-deficient cerebellum has a persistent external granular layer (EGL), rudimentary Purkinje cell (PC) dendrites, grossly reduced numbers of immature parallel fiber (PF)-PC synapses, and multiple climbing fibers (CF) innervating PCs in mice after 3 weeks of age when these features have disappeared in wild-type mice. Functionally, metabotropic glutamate receptor (mGluR)-mediated signaling in PCs is completely abrogated. Here we examined whether these defects could be corrected by lentivirally providing the ROR alpha gene to 3-week-old PCs of ROR alpha-deficient homozygous staggerer (sg/sg) mice. ROR alpha expression in sg/sg PCs significantly increased the numbers of PF-PC synapses, spines on PC dendritic branchlets, and internal granule cells, concomitant with regression of the EGL, suggesting enhanced proliferation in the EGL and migration of post-mitotic progeny into the internal granular layer with augmented synaptogenesis between PFs and PC dendrites. However, the primary dendritic stems were only slightly extended, and mGluR signaling and the loss of redundant CF synapses in sg/sg PCs remained unrestored. These results suggest that the mitogenic and migratory potential of external granule cells in response to ROR alpha was preserved in the[3-week-old sg/sg mouse cerebellum. Moreover, sg/sg PCs sprouted spines and formed synapses with PFs. However, lengthening of the primary dendritic stems, establishment of mGluR signaling, and removal of CF synapses in sg/sg PCs were regressed by 3 weeks of age.