Mechanisms of Asymmetric Cell Division During Female Meiosis

雌性减数分裂过程中不对称细胞分裂的机制

• 批准号: 10403401
• 负责人: Francis J McNally
• 金额: $ 2.72万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10403401
• 关键词: Actins; Aneuploidy; Animals; Auxins; Caenorhabditis elegans; Cell division; Centrioles; Cessation of life; Chromosome abnormality; Chromosomes; Conceptions; Cytoplasmic streaming; DNA; Defect; Deposition; Distant; Down Syndrome; Dynein ATPase; Embryo; Ensure; Female; Fertilization; Frequencies; Future; Genome; Goals; Health; Human; Image; Immobilization; Inherited; Kinesin; Lead; Meiosis; Microtubules; Mitochondria; Molecular; Monitor; Monosomy; Mosaicism; Movement; Organelles; Positioning Attribute; Public Health; RNA Interference; Research; Site; Syndrome; Time; Trisomy; Woman; chromosome conformation capture; chromosome movement; cognitive disability; cohesion; depolymerization; egg; in utero; katanin; male; offspring; optogenetics; prevent; sperm cell; zygote

Project Summary During female meiosis, ¾ of the chromosomes are eliminated and only ¼ of the chromosomes are inherited by a single egg. In contrast, all chromosomes are distributed among 4 sperm during male meiosis. The elimination of ¾ of the genome to allow inheritance of only ¼ of the chromosomes is conserved in all animal phyla, suggesting some fundamental selective advantage. The long-term goals of this project are to elucidate the molecular mechanisms of chromosome elimination and elucidate the selective advantages of asymmetric meiotic division. Errors in meiosis lead to the absence of one chromosome (monosomy) or the presence of an extra chromosome (trisomy) in 10-30% of human conceptions with the majority of these aneuploidies leading to embryonic death. By elucidating the mechanisms of meiotic chromosome elimination in C. elegans, we will identify mechanisms likely to be defective during human meiosis. Fertilization occurs during female meiosis in nearly all animal species. Therefore, animals must have mechanisms to prevent incorporation of paternal chromosomes into the meiotic spindle which could eliminate paternal chromosomes in a polar body causing lethal monosomy. We have demonstrated that, in C. elegans, microtubule driven transport moves the meiotic spindle to a cortical position away from the future site of fertilization, and that the sperm contents are immobilized at the distant site of fertilization by cortical actin. Cortical positioning of the meiotic spindle and sperm contents at opposite ends of the zygote resists cytoplasmic streaming which circulates membranous organelles around the zygote. Actin depolymerization results in movement of a cohesive unit containing sperm-derived DNA, centrioles, mitochondria and other membranous organelles with cytoplasmic streaming. However, the resulting collisions between the sperm contents and meiotic spindle do not result in incorporation of paternal chromosomes into the meiotic spindle. We seek to elucidate the completely unexplored mechanism that holds the sperm contents together as a cohesive unit, as this is both required to allow tethering to cortical actin far from the spindle and, as a backup mechanism, insulates paternal chromosomes from capture into the meiotic spindle. We have uncovered a second selective advantage of asymmetric meiosis by demonstrating that extra chromosomes present in trisomic or triploid C. elegans are preferentially deposited in a polar body. We seek to determine the mechanisms that preferentially move extra chromosomes toward the polar body. These mechanisms allow triploid or aneuploid C. elegans to have a high frequency of offspring with a normal chromosome number and could be relevant to the health prospects for offspring of women with triploX syndrome, trisomy 21 or mosaic trisomy. In addition, we will continue to elucidate the katanin, kinesin and dynein-dependent mechanisms ensuring bipolar meiotic spindle assembly and positioning. We will accomplish these goals by directly monitoring the movements of chromosomes and organelles by time-lapse imaging of zygotes observed in utero within transparent C. elegans after perturbations by RNA interference, auxin-induced degrons and optogenetic manipulations.

项目概要 在女性减数分裂期间，3/4 的染色体被消除，只有 1/4 的染色体被消除。 染色体由单个卵子遗传，相反，所有染色体都是遗传的。 在雄性减数分裂期间分布在 4 个精子中 3/4 的基因组被消除。 允许在所有动物门中仅保留 1/4 染色体的遗传， 提出了该项目的一些基本选择优势。 旨在阐明染色体消除的分子机制并阐明 不对称减数分裂的选择性优势 减数分裂错误导致。 缺少一条染色体（单体）或存在额外的染色体 （三体性）存在于 10-30% 的人类受孕中，其中大部分为非整倍体 通过阐明减数分裂染色体的机制，导致胚胎死亡。 消除秀丽隐杆线虫，我们将确定可能存在缺陷的机制 人类减数分裂几乎在所有动物物种的雌性减数分裂期间发生。 因此，动物必须具有防止父系融合的机制。 染色体进入减数分裂纺锤体，可以消除父系染色体 我们已经证明，在秀丽隐杆线虫中， 微管驱动的运输将减数分裂纺锤体移动到远离皮质的位置 未来的受精地点，并且精子内容物被固定在远处 皮质肌动蛋白的受精部位。减数分裂纺锤体和精子的皮质定位。 受精卵两端的内容物抵抗细胞质流动，从而彻底改变 受精卵周围的膜细胞器发生解聚。 含有精子衍生 DNA、中心粒、线粒体的内聚单元的运动 和其他具有细胞质流动的膜细胞器然而，由此产生的。 精子内容物和减数分裂纺锤体之间的碰撞不会导致合并 我们试图完全阐明父本染色体减数分裂纺锤体的结构。 未探索的机制将精子内容物结合在一起作为一个有凝聚力的单元，如 这既是允许束缚到远离纺锤体的皮质肌动蛋白所必需的，也是作为 备份机制，防止父本染色体被捕获进入减数分裂 我们通过纺锤体发现了不对称减数分裂的第二个选择优势。 证明三体或三倍体秀丽隐杆线虫中存在的额外染色体 我们试图确定优先沉积在极体中的机制。 优先将额外的染色体移向极体。 允许三倍体或非整倍体秀丽隐杆线虫具有高频率的具有正常特征的后代 染色体数目，可能与后代的健康前景有关 患有 TriploX 综合征、21 三体或马赛克三体的女性。 继续阐明剑蛋白、驱动蛋白和动力蛋白依赖性机制，确保 双极减数分裂纺锤体组装和定位我们将通过以下方式实现这些目标。 通过延时直接监测染色体和细胞器的运动 扰动后透明线虫子宫内观察到的受精卵成像 通过 RNA 干扰、生长素诱导的降解决定子和光遗传学操作。