A new mouse allele of glutamate receptor delta 2 with cerebellar atrophy and progressive ataxia.
A new mouse allele of glutamate receptor delta 2 with cerebellar atrophy and progressive ataxia.
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一种新的小鼠谷氨酸受体 delta 2 等位基因，伴有小脑萎缩和进行性共济失调。
DOI：
10.1371/journal.pone.0107867
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Hayasaka N
中科院分区：
文献类型：
--
作者：
Miyoshi Y;Yoshioka Y;Suzuki K;Miyazaki T;Koura M;Saigoh K;Kajimura N;Monobe Y;Kusunoki S;Matsuda J;Watanabe M;Hayasaka N
脊髓小脑变性（SCD）是一大类散发性或遗传性神经退行性疾病，其特征在于小脑和CNS其他部位的进行性运动缺陷和退行性变化。在这里，我们报告的识别和建立从C57 BL/6 J小鼠群体的一种新的小鼠线发展自发进行性共济失调，我们称之为ts 3。频率的表型表达是一致的常染色体隐性遗传孟德尔性状的遗传，这表明一个单一的基因突变是负责该线的共济失调表型。在大约三周龄时观察到共济失调的发作，其缓慢进展，直到在许多情况下后肢完全瘫痪。Micro-MRI研究显示所有共济失调小鼠均出现明显的小脑萎缩，但个体差异较大。详细的组织学分析表明，前叶的颗粒细胞（GC）减少和小脑浦肯野细胞（PC）的异常形态显着萎缩。超高压电子显微镜（UHVEM）的研究进一步表明PC树突及其棘的异常形态，表明突变体中PC的形态和功能异常。免疫组化研究还显示，平行纤维（PF）-PC突触形成和异常的远端延伸的攀爬纤维（CF）的缺陷。基于ts 3突变体与其他已知共济失调突变体的表型相似性，我们进行了免疫组织学分析，发现两个基因及其产物谷氨酸受体δ 2（grid 2）及其配体小脑蛋白1（Cbln 1）的表达水平显着降低或检测不到。最后，我们对候选基因进行了测序，并在grid 2基因的编码区检测到一个大的缺失。我们目前的研究表明，ts 3是一个新的等位基因的grid 2基因，这导致类似的，但不同的表型相比，其他grid 2突变体。
Spinocerebellar degenerations (SCDs) are a large class of sporadic or hereditary neurodegenerative disorders characterized by progressive motion defects and degenerative changes in the cerebellum and other parts of the CNS. Here we report the identification and establishment from a C57BL/6J mouse colony of a novel mouse line developing spontaneous progressive ataxia, which we refer to as ts3. Frequency of the phenotypic expression was consistent with an autosomal recessive Mendelian trait of inheritance, suggesting that a single gene mutation is responsible for the ataxic phenotype of this line. The onset of ataxia was observed at about three weeks of age, which slowly progressed until the hind limbs became entirely paralyzed in many cases. Micro-MRI study revealed significant cerebellar atrophy in all the ataxic mice, although individual variations were observed. Detailed histological analyses demonstrated significant atrophy of the anterior folia with reduced granule cells (GC) and abnormal morphology of cerebellar Purkinje cells (PC). Study by ultra-high voltage electron microscopy (UHVEM) further indicated aberrant morphology of PC dendrites and their spines, suggesting both morphological and functional abnormalities of the PC in the mutants. Immunohistochemical studies also revealed defects in parallel fiber (PF)–PC synapse formation and abnormal distal extension of climbing fibers (CF). Based on the phenotypic similarities of the ts3 mutant with other known ataxic mutants, we performed immunohistological analyses and found that expression levels of two genes and their products, glutamate receptor delta2 (grid2) and its ligand, cerebellin1 (Cbln1), are significantly reduced or undetectable. Finally, we sequenced the candidate genes and detected a large deletion in the coding region of the grid2 gene. Our present study suggests that ts3 is a new allele of the grid2 gene, which causes similar but different phenotypes as compared to other grid2 mutants.
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影响因子：
11.4
作者：
Hoehn, Annika;Grune, Tilman
通讯作者：
Grune, Tilman
影响因子：
56.9
作者：
Matsuda, Keiko;Miura, Eriko;Yuzaki, Michisuke
通讯作者：
Yuzaki, Michisuke
DOI：
10.1038/nrn2946
发表时间：
2011-01
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Blackstone C;O'Kane CJ;Reid E
通讯作者：
Reid E
DOI：
10.1097/wno0b013e3181b416de
发表时间：
2009-09
期刊：
Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society
影响因子：
--
作者：
Paulson HL
通讯作者：
Paulson HL
影响因子：
2.9
作者：
Grossman, Aaron W.;Elisseou, Nicholas M.;Greenough, William T.
通讯作者：
Greenough, William T.