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: 10359713
• 负责人: Francis J McNally
• 金额: $ 38.8万
• 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/10359713
• 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.

项目摘要 在女性减数分裂过程中，¾染色体被消除，只有1/4 染色体是由一个鸡蛋遗传的。相反，所有染色体都是 在男性减数分裂过程中分布在4个精子中。消除¾基因组 仅允许遗传¼染色体在所有动物门中都保守 提出一些基本的选择性优势。该项目的长期目标 阐明消除染色体的分子机制并阐明 不对称减数分裂部门的选择性优势。减数分裂的错误导致 不存在一个染色体（单色）或额外的染色体的存在 （三体）在10-30％的人类概念中，大多数这些非整倍性 导致胚胎死亡。通过阐明减数分裂染色体的机制 在秀丽隐杆线虫中取消，我们将确定可能有缺陷的机制 人类减数分裂。在几乎所有动物物种的女性减数分裂过程中，受精发生。 因此，动物必须具有防止父亲掺入的机制 进入减数分裂主轴的染色体，可以消除在 极性体引起致命的单肌。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至皮质位置远离 未来的受精部位，精子含量在遥远的 皮质肌动蛋白受精部位。减数分裂主轴和精子的皮质定位 合子反应物的相反端的含量细胞流的圆形流 合子周围的膜细胞器。肌动蛋白沉积导致 含有精子DNA，中心和线粒体的粘性单元的运动 和其他带有细胞质流的膜细胞器。但是，由此产生 精子内容与减数分裂主轴之间的碰撞不会导致收入 染色体进入减数分裂纺锤体。我们寻求完全阐明 意外的机制将精子内容固定在一起，作为一个粘性单元 这既需要允许绑住皮质肌动蛋白远离纺锤体，并且作为一个 备用机制，将父亲染色体从捕获到减数分裂中绝缘 主轴。我们发现了不对称减数分裂的第二个选择性优势 证明trisomic或三倍体秀丽隐杆线虫中存在的额外染色体是 优先沉积在极体中。我们试图确定 优先将额外的染色体移向极性体。这些机制 允许三倍体或非倍型秀丽隐杆线虫具有正常的高频率后代 染色体编号，可能与健康前景有关 患有三重综合征的女性，三体疾病或马赛克三体。此外，我们将 继续阐明Katanin，驱动蛋白和动力蛋白依赖性机制，以确保 双极减数分裂主轴组件和定位。我们将通过 直接通过延时监测染色体和细胞器的运动 扰动后透明秀丽隐杆线虫在子宫内观察到的合子成像 通过RNA干扰，生长素诱导的脱氧基因和光遗传操作。