Mechanisms of asymmetric cell division during female meiosis.

描述(申请人提供)：在雌性减数分裂过程中，3/4的染色体被消除，只有1/4的染色体被单个卵子遗传。相反，在雄性减数分裂过程中，所有的染色体都分布在4个精子中。消除3/4的基因组，只允许1/4的染色体遗传，在所有动物门中都是保守的，这表明了一些基本的选择优势。该项目的长期目标是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。减数分裂中的错误导致10-30%的人类胚胎中缺少一条染色体(单体)或存在额外的染色体(三体)，这些非整倍体中的大多数会导致胚胎死亡。通过阐明线虫减数分裂染色体消除的机制，我们将识别在人类减数分裂过程中可能存在缺陷的机制。在这个项目中，我们将追求4个具体目标：1.阐明阻止精子浆捕获卵母细胞减数分裂纺锤体的机制。2.确定细胞质动力蛋白如何将一个纺锤体极定向到大脑皮层。3.确定Katanin如何调节无着丝点纺锤体极组装。4.测试未配对的染色体是否被选择性地挤入极体，以防止三体。这些目标将通过对减数分裂胚胎内荧光蛋白融合的延时成像来实现，减数分裂胚胎已经由于RNA干扰和蛋白质生物化学而失去了关键的细胞骨架调节因子和细胞周期调节因子。 与公共卫生相关：拟议的研究与公共健康相关，因为在10%-30%的人类受孕中，染色体缺失或存在额外的染色体。这些染色体异常大多是由雌性减数分裂过程中的缺陷引起的，这些染色体异常会导致胚胎死亡或智力低下。这项拟议的研究将揭示可能导致人类这些异常的机制，并将提出防止它们的方法。

DESCRIPTION (provided by applicant): During female meiosis, 3/4 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. In this project we will pursue 4 specific aims: 1. Elucidate mechanisms that prevent the sperm aster from capturing the oocyte meiotic spindle. 2. Determine how cytoplasmic dynein orients one spindle pole at the cortex. 3. Determine how katanin mediates acentriolar spindle pole assembly. 4. Test whether unpaired chromosomes are selectively extruded into polar bodies to prevent trisomy. These aims will be addressed by time-lapse imaging of fluorescent protein fusions within meiotic embryos that have been depleted of key cytoskeletal regulators and cell-cycle regulators by RNA interference and by protein biochemistry. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because chromosomes are missing or an extra chromosome is present in 10-30% of human conceptions. The majority of these chromosomal abnormalities are caused by defects during female meiosis and these chromosomal abnormalities lead to embryonic death or mental retardation. The proposed research will reveal mechanisms that may cause these abnormalities in humans and will suggest ways to prevent them.