Pronuclear rotation in the C. elegans embryo

线虫胚胎中的原核旋转

• 批准号: 9409304
• 负责人: Valerie Chest Coffman
• 金额: $ 0.02万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9409304
• 关键词: Acceleration; Affect; Animal Model; Anterior; Biochemical; Biological; Biological Process; Caenorhabditis elegans; Cancerous; Cell Cycle; Cell Nucleus; Cell Polarity; Cell Separation; Cell division; Cells; Centrioles; Centrosome; Chromosome Segregation; Chromosomes; Complex; Coupled; Cues; Cytoplasm; Data; Defect; Disease; Disseminated Malignant Neoplasm; Dorsal; Dynein ATPase; Embryo; Ensure; Epithelial Cells; Eukaryota; Event; Exhibits; Female; Fertilization; Foundations; Genetic; Goals; Hela Cells; Lead; Learning; Length; Link; Malignant Neoplasms; Mechanics; Mediating; Membrane; Microtubule-Associated Proteins; Microtubule-Organizing Center; Microtubules; Minus End of the Microtubule; Mitotic spindle; Modeling; Molecular; Motor; Movement; Nematoda; Normal Cell; Nuclear; Outcome; Plus End of the Microtubule; Positioning Attribute; Preparation; Proteins; RNA Interference; Radial; Reporting; Research; Rotation; Solid Neoplasm; Source; Spatial Distribution; Specific qualifier value; Techniques; Testing; Tissues; Torque; Tumor Tissue; Work; base; cancer cell; embryo cell; human stem cells; in vivo; male; mathematical model; mechanical force; mechanical properties; novel; nuclear division; physical model; polarized cell; prevent; public health relevance; response; segregation; simulation; sperm cell; stem cell biology; therapeutic target; tool; tumor progression; zygote

 DESCRIPTION (provided by applicant): Cells found in solid tumors differ from healthy cells in a number of ways; notably cancerous cells often exhibit a loss of polarity and the resulting tumor tissues are highly disorganized. Tissue organization arises from precise control of the orientation of cell division which is mediated by microtubules and microtubule-associated proteins. The mitotic spindle, which originates at the nuclear position and is composed of microtubules, aligns perpendicular to the cleavage furrow to ensure proper segregation of cytoplasmic and nuclear materials. Asymmetric division results from asymmetric spatial distribution of cellular components prior to division. Despite the importance of mitotic spindle positioning in specifying the division plane, the mechanics and interactions that link cell polarit cues to the spindle position are unclear. The C. elegans zygote is an ideal model organism for studying the mechanics of spindle positioning because genetic and molecular techniques are well developed. In the single-celled embryo, the female and male pronuclei meet near the posterior and are translocate to the middle of the embryo while simultaneously rotating. Thus, the spindle axis aligns with the anterior/posterior polarity axis of the cell, giving rise to anteror and posterior specified fates after the first division. Studies of spindle orientation have assumed that asymmetric localization of force generators induces torque for spindle rotation. However, mathematical modeling of known interactions between polarity proteins and microtubules results in centering of the nucleus but not rotation. Rotation depends on the microtubule plus-end motor protein dynein; however, dynein is located symmetrically throughout the embryo. Moreover, dynein regulators are localized either anteriorly or posteriorly, but with radial symmetry. Two mechanisms that are not mutually exclusive, might contribute to rotation. The first is that some protein affecting the pulling force of dynein on microtubules is radially asymmetric, leading to more force acting on one of the centrosomes. The second mechanism is that the centrosomes do not respond equally to the force from dynein. The central hypothesis of this proposal is that rotation can be explained by radially asymmetric cortical forces acting on the centrosomes coupled with a maturation-dependent difference in the way centrosomes respond to cortical forces. This hypothesis will be tested with three specific aims: 1) Generate mathematical models of the rotation event to test the two mechanisms of rotation. 2) Investigate the maturation-dependent differences between the two centrosomes. And 3) Using a candidate approach, uncover the radially asymmetric regulator(s) of dynein activity. This research is significant because it will lay the foundation for important questions in cancer and stem cell biology. Mathematical and physical modeling has contributed to our understanding of many biological processes. Models not only help to summarize key data, but also offer predictive power to generate novel hypotheses that can be tested in vivo.

 描述（由申请人提供）：实体瘤中发现的细胞在许多方面与健康细胞不同；值得注意的是，癌细胞通常表现出极性丧失，并且由此产生的肿瘤组织高度混乱。由微管和微管相关蛋白介导的细胞分裂 有丝分裂纺锤体起源于核位置并由微管组成，垂直于分裂排列。尽管有丝分裂纺锤体定位在指定分裂平面中很重要，但将细胞极性线索与纺锤体联系起来的机制和相互作用是由分裂前细胞成分的不对称空间分布引起的。线虫受精卵是研究纺锤体定位机制的理想模型生物，因为遗传和分子技术在单细胞胚胎中相遇。纺锤体轴与细胞的前/后极性轴对齐，从而在第一次分裂后产生前部和后部特定的命运。已经假设 力发生器的不对称定位会引起主轴旋转的扭矩，但是，极性蛋白和微管之间已知相互作用的数学模型导致细胞核居中，但旋转取决于微管加端运动蛋白动力蛋白。此外，动力蛋白调节器位于前部或后部，但具有径向对称性，这两种机制并不相互排斥，可能有助于旋转。第一个机制是影响动力蛋白对微管的拉力的某些蛋白质是径向不对称的，导致作用在其中一个中心体上的力更大。第二个机制是中心体对动力蛋白的作用力的反应不相等。该提议认为，旋转可以通过作用在中心体上的径向不对称皮质力以及中心体对皮质力反应方式的成熟依赖性差异来解释。该假设将得到检验。具有三个具体目标：1）生成旋转事件的数学模型以测试两种旋转机制；2）研究两个中心体之间的成熟依赖性差异；3）使用候选方法，揭示径向不对称调节因子。这项研究意义重大，因为它将为癌症和干细胞生物学的重要问题奠定基础。模型不仅有助于总结关键数据，而且有助于我们理解许多生物过程。还提供预测能力来产生可在体内测试的新假设。