Mechanisms of asymmetric cell division during female meiosis

女性减数分裂过程中不对称细胞分裂的机制

• 批准号: 10794135
• 负责人: Francis J McNally
• 金额: $ 23.48万
• 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/10794135
• 关键词: Actins; Aneuploidy; Animals; Auxins; Caenorhabditis elegans; Cell division; Centrioles; Chromosome Segregation; Chromosome abnormality; Chromosomes; Clustered Regularly Interspaced Short Palindromic Repeats; Conceptions; Cytoplasmic streaming; Cytoskeleton; DNA; Defect; Deposition; Distant; Down Syndrome; Dynein ATPase; Embryo Deaths; Ensure; Event; Female; Fertilization; Frequencies; Future; Genome; Goals; Health; Human; Image; Immobilization; Inherited; Kinesin; Knock-out; Lead; Meiosis; Microtubules; Mitochondria; Molecular; Monitor; Monosomy; Mothers; Movement; Oocytes; Organelles; Outcome; Positioning Attribute; Production; Public Health; RNA Interference; Reproductive Biology; Research; Site; Spermatocytes; Syndrome; System; Trisomy; Woman; chromosome conformation capture; chromosome movement; cognitive disability; depolymerization; egg; genetic manipulation; in utero; katanin; live cell imaging; male; mosaic; offspring; optogenetics; prevent; sperm cell; zygote

Project Summary During female meiosis, ¾ of the chromosomes are eliminated and only 1/4 of the chromosomes are inherited by a single egg. In contrast, all chromosomes are distributed among 4 sperm during male meiosis. The elimination of 3/4 of the genome to allow inheritance of only 1/4 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 在雌性减数分裂期间，3/4的染色体被消除，只有1/4的染色体被破坏。 染色体由单个卵子继承。相比之下，所有染色体都是 在雄性减数分裂时分布在4个精子中。消除3/4的基因组， 允许遗传的只有1/4的染色体在所有动物门中是保守的， 暗示着某种基本的选择优势本项目的长期目标 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）或存在额外染色体 在10-30%的人类受孕中，大多数是非整倍体 导致胚胎死亡。通过阐明减数分裂染色体的机制， 消除C。我们将确定可能存在缺陷的机制， 人类减数分裂几乎所有动物的受精都发生在雌性减数分裂期间。 因此，动物必须有机制，以防止纳入父亲的 染色体进入减数分裂纺锤体，这可能会消除父本染色体， 极体导致致命的单体。我们已经证明，在C。优雅， 微管驱动的运输将减数分裂纺锤体移动到皮质位置， 未来的受精位点，精子内容物被固定在远处， 通过皮层肌动蛋白受精的部位。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， 受精卵周围的膜质细胞器。肌动蛋白解聚导致 含有精子来源的DNA、中心粒、线粒体的粘性单位的运动 以及其他具有细胞质流的膜细胞器。但是，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结合 进入减数分裂纺锤体。我们寻求彻底阐明 一种未被探索的机制，将精子内容物作为一个内聚单位保持在一起， 这是允许束缚到远离纺锤体的皮层肌动蛋白所必需的， 备份机制，使父本染色体不被捕获进入减数分裂 纺锤体。我们已经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C.优雅的是 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体。这些机制 允许三倍体或非整倍体C.有一个正常的后代的频率很高， 染色体数目，可能与后代的健康前景有关。 患有三倍体X综合征、21三体或镶嵌三体的女性。此外，我们将 继续阐明katanin，驱动蛋白和动力蛋白依赖的机制， 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 在透明C.扰动后的秀丽隐杆线虫 通过RNA干扰、生长素诱导的降解决定子和光遗传学操作。