CTCF loss induces giant lamellar bodies in Purkinje cell dendrites.
CTCF loss induces giant lamellar bodies in Purkinje cell dendrites.
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DOI：
10.1186/s40478-022-01478-6
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发表时间：
2022-11-29
影响因子：
7.1
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中科院分区：
文献类型：
--
作者：
CCCTC结合因子（CTCF）在高级染色质结构中具有关键作用，其对于通过控制基因表达来建立和维持细胞身份是重要的。在成熟的小脑中，CTCF在浦肯野细胞（PC）中高度表达，与其他小脑神经元相比。小脑通过调节PC在运动功能中起重要作用，PC是唯一的输出神经元，并且PC的缺陷导致运动功能障碍。然而，CTCF在PC中的作用尚未被探索。在这里，我们发现，CTCF在小鼠PC中的情况下，导致进行性运动功能障碍和异常的树突形态在这些细胞中，其中包括树突自我回避缺陷和近端移位的PC树突上的攀爬纤维神经支配领土。此外，我们发现了被称为“巨板层体”（GLB）的奇特板层结构，这已在Werdnig-Hoffman病，13 q缺失综合征和Krabbe病患者的PC中报道。GLB定位于PC树突，并被认为与神经变性有关。然而，只有在尸检后的病例报告中才注意到它们，关于它们存在的报告非常有限。在这里，我们表明GLB在CTCF缺失的小鼠模型的PC树突中可重复地形成。GLB在婴儿期PC树突中没有发现，而是随着时间的推移而发展。在PC树突GLB的发展，内质网几乎是不存在的核周围，线粒体显着肿胀，其嵴急剧下降，几乎所有的PC最终消失，表现为严重的运动缺陷。我们的研究结果揭示了CTCF在正常发育和维持PC中的重要作用，并为神经退行性疾病期间GLB形成的分子机制提供了新的见解。在线版本包含补充材料，可通过10.1186/s40478-022-01478-6获得。
CCCTC-binding factor (CTCF) has a key role in higher-order chromatin architecture that is important for establishing and maintaining cell identity by controlling gene expression. In the mature cerebellum, CTCF is highly expressed in Purkinje cells (PCs) as compared with other cerebellar neurons. The cerebellum plays an important role in motor function by regulating PCs, which are the sole output neurons, and defects in PCs cause motor dysfunction. However, the role of CTCF in PCs has not yet been explored. Here we found that the absence of CTCF in mouse PCs led to progressive motor dysfunction and abnormal dendritic morphology in those cells, which included dendritic self-avoidance defects and a proximal shift in the climbing fibre innervation territory on PC dendrites. Furthermore, we found the peculiar lamellar structures known as “giant lamellar bodies” (GLBs), which have been reported in PCs of patients with Werdnig-Hoffman disease, 13q deletion syndrome, and Krabbe disease. GLBs are localized to PC dendrites and are assumed to be associated with neurodegeneration. They have been noted, however, only in case reports following autopsy, and reports of their existence have been very limited. Here we show that GLBs were reproducibly formed in PC dendrites of a mouse model in which CTCF was deleted. GLBs were not noted in PC dendrites at infancy but instead developed over time. In conjunction with GLB development in PC dendrites, the endoplasmic reticulum was almost absent around the nuclei, the mitochondria were markedly swollen and their cristae had decreased drastically, and almost all PCs eventually disappeared as severe motor deficits manifested. Our results revealed the important role of CTCF during normal development and in maintaining PCs and provide new insights into the molecular mechanism of GLB formation during neurodegenerative disease. The online version contains supplementary material available at 10.1186/s40478-022-01478-6.
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影响因子：
64.5
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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作者：
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