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 在雌性减数分裂过程中，3/4的染色体被消除，只有1/4的染色体 染色体是由一个卵子遗传的。相反，所有的染色体都是 在雄性减数分裂过程中分布在4个精子中。消除了3/4的基因组 允许遗传的染色体只有1/4在所有动物门中都是保守的， 暗示了一些根本性的选择性优势。这个项目的长期目标是 是为了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优势。减数分裂的错误导致 缺少一条染色体(单体)或存在额外的染色体 (三体)在10%-30%的人类受孕中，这些非整倍体占大多数 导致胚胎死亡。通过阐明减数分裂染色体的机制 为了消除线虫，我们将确定可能存在缺陷的机制 人类减数分裂。在几乎所有的动物物种中，受精都发生在雌性减数分裂期间。 因此，动物必须有防止父亲合并的机制 染色体进入减数分裂纺锤体，这可以消除父亲的染色体在一个 导致致命性单体的极体。我们已经证明，在线虫身上， 微管驱动的运输将减数分裂纺锤体移动到远离 未来的受精地点，精子内容物被固定在遥远的地方 皮质肌动蛋白受精的部位。减数分裂纺锤体和精子的皮质定位 合子两端的内容物阻止了细胞质流动的循环 合子周围的膜质细胞器。肌动蛋白解聚导致 包含精子衍生DNA、中心粒、线粒体的凝聚力单位的运动 和其他细胞器具有细胞质流动。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并入 父亲的染色体进入减数分裂纺锤体。我们试图彻底地阐明 未探索的将精子内容物作为一个凝聚单元保持在一起的机制，如 这既是允许连接到远离纺锤体的皮质肌动蛋白所必需的，也是作为一种 备份机制，使父本染色体不被捕获进入减数分裂 纺锤形。我们发现了不对称减数分裂的第二个选择性优势 证明在三体或三倍体线虫中存在额外的染色体 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体。这些机制 允许三倍体或非整倍体线虫有较高频率的后代 染色体数目，并可能与后代的健康前景有关 患有三倍体综合征、21三体或马赛克三体的女性。此外，我们还将 继续阐明katanin、kinesin和dynein依赖的机制，确保 两极减数分裂纺锤体的组装和定位。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 透明线虫扰动后子宫内观察受精卵的成像 通过RNA干扰、生长素诱导的退化和光遗传操作。