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Characterisation of genes that regulate centriole stability and ciliogenesis

调节中心粒稳定性和纤毛发生的基因的表征

基本信息

批准号：
RGPIN-2017-06470
负责人：
Roy, Richard
金额：
$ 2.04万
依托单位：
McGill University
依托单位国家：
加拿大
项目类别：
Discovery Grants Program - Individual
财政年份：
2020
资助国家：
加拿大
起止时间：
2020-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=711388
关键词：
Characterisation genes regulate centriole stability

项目摘要

The chromosome segregation that occurs during most mitotic divisions is accomplished largely by forces generated by microtubules. In most cases these microtubules emanate from the centrosome-based microtubule organising centre. The centrosome is a complex structure that comprises a centriole pair surrounded by a proteinaceous nuage referred to as the pericentriolar material. At each mitotic cell division the centriole pair must split, duplicate and separate to opposing poles of the spindle in what is referred to as the centrosome cycle. However when cells cease their divisions to execute their terminal differentiation program the centrioles too must recognize this condition and accordingly arrest the centrosome cycle. Following the final division in mammalian epithelial cells the unduplicated centrioles present in the daughter cells undergo specific changes and migrate to the cell membrane where they will generate the primary cilium. These organelles are extensions of the cell membrane and can contribute to cell motility, mechanotransduction, while also playing a central role in cell signalling. In C. elegans, cilia are restricted to the sensory neurons; differentiated epithelial cells do not possess primary cilia nor do they show evidence of a centriole/centrosome. We have shown that in specific developmental contexts the centrioles uncouple from the cell cycle, while in the epithelial cells of the gut, the vulva, and the hypodermis, the centrioles are actively eliminated following the final cell division. The epithelial cells of C. elegans therefore do not possess primary cilia potentially because their centrioles are actively eliminated upon terminal differentiation. To investigate the process involved in centriole elimination following the final division we genetic analysis to identify mutants that do not eliminate their centrioles upon differentiation. Using a centriole-specific marker we sought to isolate mutants that disrupted the timely elimination of the centrioles in differentiated epithelia, namely in the intestine. From this pilot screen we identified one mutant that allows the centrioles to persist in the gut epithelial cells in C. elegans. These centrioles however do not become cilia suggesting that the presence of a post-mitotic centriole is not sufficient for the formation of a cilium. We will use by classic genetic analysis and novel transgenic approaches to identify genes that may block this conversion or are required to convert a mitotic centriole into a cilium.

在大多数有丝分裂中发生的染色体分离主要是由微管产生的力完成的。在大多数情况下，这些微管从基于中心体的微管组织中心发出。中心体是一个复杂的结构，它包括一对中心粒，周围有一层蛋白质样的颗粒，称为中心粒周物质。在每次有丝分裂时，中心粒对必须分裂、复制并分离到纺锤体的相对两极，这被称为中心体周期。然而，当细胞停止分裂以执行其终末分化程序时，中心粒也必须认识到这种情况，并相应地阻止中心体循环。在哺乳动物上皮细胞的最终分裂之后，存在于子细胞中的未复制的中心粒经历特定的变化并迁移到细胞膜，在那里它们将产生初级纤毛。这些细胞器是细胞膜的延伸，可以促进细胞运动，机械转导，同时也在细胞信号传导中发挥核心作用。 In C.在elegans中，纤毛仅限于感觉神经元;分化的上皮细胞不具有初级纤毛，也不显示中心粒/中心体的证据。我们已经表明，在特定的发育背景下，中心粒从细胞周期中分离，而在肠，外阴和皮下组织的上皮细胞中，中心粒在最终的细胞分裂后被积极消除。C.因此，秀丽线虫可能不具有初级纤毛，因为它们的中心粒在终末分化时被主动消除。为了研究最终分裂后中心粒消除的过程，我们进行了遗传分析，以鉴定在分化时不消除中心粒的突变体。使用中心粒特异性标记，我们试图分离突变体，破坏及时消除分化上皮细胞中的中心粒，即在肠。从这个初步筛选中，我们鉴定了一个突变体，它允许中心粒在C.优美的然而，这些中心粒不成为纤毛，这表明有丝分裂后中心粒的存在不足以形成纤毛。我们将通过经典的遗传分析和新的转基因方法来鉴定可能阻止这种转换或将有丝分裂中心粒转换为纤毛所需的基因。