The Spontaneous Ataxic Mouse Mutant Tippy is Characterized by a Novel Purkinje Cell Morphogenesis and Degeneration Phenotype.
The Spontaneous Ataxic Mouse Mutant Tippy is Characterized by a Novel Purkinje Cell Morphogenesis and Degeneration Phenotype.
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DOI：
10.1007/s12311-014-0640-x
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发表时间：
2015-06
期刊：
影响因子：
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通讯作者：
Millen KJ
中科院分区：
文献类型：
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作者：
Shih EK;Sekerková G;Ohtsuki G;Aldinger KA;Chizhikov VV;Hansel C;Mugnaini E;Millen KJ
这项研究代表了第一个详细的分析自发神经小鼠突变体，tippy，揭示其独特的小脑表型。纯合子tippy突变小鼠体型小，共济失调，在断奶前后死亡。虽然小脑显示大体上正常的叶状，tippy突变体显示一个复杂的小脑浦肯野细胞表型组成的异常树突状分支与不成熟的棘功能和斑片状，非凋亡性细胞死亡，与广泛的营养不良和变性的浦肯野细胞轴突整个白色物质，小脑核和前庭核。中度解剖异常的攀爬纤维神经支配的tippy突变体浦肯野细胞与攀爬纤维EPSC振幅的变化无关。然而，ESPC振幅下降，观察到平行纤维刺激和相关的解剖证据斑片状暗细胞变性的浦肯野细胞树突的分子层。这些数据表明，浦肯野神经元是tippy突变的主要目标。此外，我们假设浦肯野细胞轴突病理连同小脑皮质中的攀爬纤维和平行纤维浦肯野细胞输入的平衡中断是这些小鼠共济失调表型的基础。浦肯野细胞树突状细胞畸形和变性表型的星座在tippy突变体是独特的，并没有在任何其他神经系统突变的报道。将tippy突变精细定位到远端9号染色体的2.1MB区域，该区域不包括先前涉及小脑发育或神经元变性的任何基因，证实了tippy突变识别了新的生物学和基因功能。
This study represents the first detailed analysis of the spontaneous neurological mouse mutant, tippy, uncovering its unique cerebellar phenotype. Homozygous tippy mutant mice are small, ataxic and die around weaning. Although the cerebellum shows grossly normal foliation, tippy mutants display a complex cerebellar Purkinje cell phenotype consisting of abnormal dendritic branching with immature spine features and patchy, non-apoptotic cell death that is associated with widespread dystrophy and degeneration of the Purkinje cell axons throughout the white matter, the cerebellar nuclei and the vestibular nuclei. Moderate anatomical abnormalities of climbing fiber innervation of tippy mutant Purkinje cells were not associated with changes in climbing fiber-EPSC amplitudes. However, decreased ESPC amplitudes were observed in response to parallel fiber stimulation and correlated well with anatomical evidence for patchy dark cell degeneration of Purkinje cell dendrites in the molecular layer. The data suggest that the Purkinje neurons are a primary target of the tippy mutation. Furthermore, we hypothesize that the Purkinje cell axonal pathology together with disruptions in the balance of climbing fiber and parallel fiber Purkinje cell input in the cerebellar cortex underlie the ataxic phenotype in these mice. The constellation of Purkinje cell dendritic malformation and degeneration phenotypes in tippy mutants is unique and has not been reported in any other neurologic mutant. Fine mapping of the tippy mutation to a 2.1MB region of distal chromosome 9, which does not encompass any gene previously implicated in cerebellar development or neuronal degeneration, confirms that the tippy mutation identifies novel biology and gene function.