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The relationship between Rab11-endosomes and the centrosome during division

Rab11-核内体和中心体在分裂过程中的关系

基本信息

批准号：
10431951
负责人：
Heidi Hehnly
金额：
$ 31.5万
依托单位：
SYRACUSE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-03 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10431951
关键词：
3-Dimensional Acinus organ component Address Animal Model Apical Attention Binding Biosensor Cell Culture Techniques Cell Cycle Cell division Cell membrane Cells Centrioles Centrosome Cilia Congenital Heart Defects Cyst Cytokinesis DNA Sequence Alteration Defect Dependence Development Disease Dissociation Distal Endosomes Event Fluorescence Resonance Energy Transfer Genes Guanosine Triphosphate Phosphohydrolases Hair Interphase Kidney Left Link Liver Measures Membrane Microtubules Mitotic Mitotic spindle Modeling Molecular Monitor Monomeric GTP-Binding Proteins Morphogenesis Mothers Oranges Organ Organelles Pancreas Pathway interactions Patients Play Positioning Attribute Process Proteins Recycling Role Signal Transduction Site Structure Testing Time Tissues Tubular formation Vertebrates Vesicle Zebrafish apical membrane appendage base cell assembly cell type ciliopathy cilium biogenesis cilium motility fluid flow in vivo kidney cell kidney epithelial cell kinetosome live cell imaging optogenetics rab GTP-Binding Proteins tool vesicle transport

项目摘要

SUMMARY STATEMENT: Ciliopathies comprise a group of disorders associated with genetic mutations encoding defective proteins, which result in either abnormal formation or function of cilia. Ciliopathies have been linked to defects in molecular pathways organized at the primary cilium's basal body/centrosome and the primary cilium itself. Patients suffering from ciliopathies can display defects in left/right asymmetry, congenital cardiac defects, and formation of cysts in multiple organs including liver, pancreas and kidney. In vertebrates, motile cilia located in an organ of asymmetry play an important role in left-right development. Evidence from model organisms, such as zebrafish organ of asymmetry (Kupffer's Vesicle, KV), indicates that conserved cilia-driven left-right flow establishes left- right signals to regulate target genes to control left/right asymmetry. This project addresses the question: How do ciliated cells develop into a functional polarized organ? We propose this occurs through a sequential process that starts with cell division, polarity formation, and finishes with cilia assembly. If a ciliated organ wants to expand its central lumen, cells need to re-enter the cell cycle and correctly position its mitotic spindle along the longest axis parallel to the expanding lumen. We found that both Rab11-associated endosomes and a centrosome protein, cenexin, regulate the positioning of the mitotic spindle and ciliogenesis (Hehnly and Doxsey, 2014; Hung et al., 2016), but whether they act together during these processes has not been examined. During interphase, Rab11-endosomes associate with mother centriole sub-distal appendages where cenexin resides (Hehnly et al., 2012). Rab11 and a second GTPase, Rab8, can directly interact with cenexin. In addition, a GTPase cascade has been identified between Rab11 and Rab8 during ciliogenesis and apical membrane initiation, but if it requires the centrosome or occurs during specific points of the cell cycle is unknown. We will test the overall hypothesis that anchoring Rab11 and/or Rab8 by the mother centriole appendage protein, cenexin, is required for spindle positioning, polarity formation and/or ciliogenesis. To test this we will determine whether the centrosome can modulate Rab11 and/or Rab8 activity (Aim 1) and determine when during the cell cycle Rab11 and Rab8 activity is required to regulate tissue morphogenesis (Aim 2). This will be accomplished by using a 3-D kidney epithelial cell culture model and an in vivo developmental model, zebrafish KV formation, to identify a framework for how polarity formation relates to the cell cycle.!

摘要陈述：纤毛疾病包括一组与遗传相关的疾病突变编码有缺陷的蛋白质，导致纤毛的异常形成或功能。纤毛病变与初级纤毛底部组织的分子通路缺陷有关身体/中心体和初级纤毛本身。患有纤毛疾病的患者可以表现出左/右不对称，先天性心脏缺陷，以及多个器官的囊性形成，包括肝脏、胰腺和肾脏。在脊椎动物中，位于不对称器官中的活动纤毛起着在左右发展中发挥重要作用。来自模式生物的证据，如斑马鱼器官不对称性(库普弗氏囊泡，KV)，表明保守的纤毛驱动的左向右血流建立了左-右血流。右信号调节靶基因，控制左/右不对称。该项目针对的是问：纤毛细胞是如何发育成功能极化的器官的？我们认为这种情况会发生经过一系列的过程，从细胞分裂开始，形成极性，最后形成纤毛集合。如果纤毛器官想要扩大其中央管腔，细胞需要重新进入细胞周期并沿着与扩张的管腔平行的最长轴正确定位其有丝分裂纺锤体。我们发现与Rab11相关的内切体和中心体蛋白cenexin都调节有丝分裂纺锤体和纤毛发生(Hehnly和Doxsey，2014；Hung等人，2016)，但它们是否起作用在这些过程中的共同作用还没有得到审查。在间期，Rab11-内涵体与cenexin所在的母中心粒亚远端附属物伴生(Hehnly等人，2012年)。 Rab11和第二个GTP酶Rab8可以直接与cenexin相互作用。此外，GTPase级联在纤毛发生和顶膜起始过程中发现了Rab11和Rab8之间的基因，但如果它需要中心体或发生在细胞周期的特定点是未知的。我们将测试总体假设是通过母中心粒附属蛋白锚定Rab11和/或Rab8， Cenexin是纺锤体定位、极性形成和/或纤毛发生所必需的。为了测试这一点，我们将确定中心体是否能够调节Rab11和/或Rab8的活性(目标1)并确定在细胞周期中，需要Rab11和Rab8活性来调节组织形态发生(目的 2)。这将通过使用3D肾上皮细胞培养模型和体内发展模型，斑马鱼KV形成，以确定极性形成如何相关的框架进入细胞周期。！

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The centrosome - diverse functions in fertilization and development across species.

DOI：
10.1242/jcs.261387
发表时间：
2023-12-01
期刊：
Journal of cell science
影响因子：
4
作者：
通讯作者：

Rab11 endosomes and Pericentrin coordinate centrosome movement during pre-abscission in vivo.

DOI：
10.26508/lsa.202201362
发表时间：
2022-07
期刊：
Life science alliance
影响因子：
4.4
作者：
Krishnan N;Swoger M;Rathbun LI;Fioramonti PJ;Freshour J;Bates M;Patteson AE;Hehnly H
通讯作者：
Hehnly H

Rab8, Rab11, and Rab35 coordinate lumen and cilia formation during zebrafish left-right organizer development.