Metotic Spindle Assembly and Aneuploidy in Mammals

描述（由申请人提供）：据估计， 所有人类的概念是染色体异常（非整倍体），许多 这些异常的发生是由于染色体分离的错误， 雌性减数分裂非整倍体最强的预测因子之一是母亲的年龄 在40岁以上的女性中，将近一半的卵母细胞排卵含有错误 染色体数目。大多数非整倍体妊娠在出生前死亡，但也有一些非整倍体妊娠在出生前死亡。 特定的非整倍体状态（例如21三体）是可行的，作为一类， 是人类智力迟钝的最常见原因。尽管如此， 临床上的重要性，很少有人知道的原因，染色体 在雌性减数分裂期间不分离或者为什么不分离的比率 随着母亲年龄的增长。 一个模型被提出来解释母亲年龄和 染色体不分离的频率表明， 卵泡发生（卵泡中卵母细胞的发育） 卵巢）在老年妇女中减少。我们假设减少或受损的 卵泡发生可能通过减少染色体的不分离而促进染色体的不分离。 排列所需的特定微管马达蛋白的量 和/或染色体在减数分裂纺锤体上的分离。为了验证这一 假设，我们建议使用转基因小鼠技术， 干扰女性生殖过程中驱动蛋白相关蛋白Kid和MCAK的功能 减数分裂我们把基德和麦克阿克作为目标是因为 整个纺锤体组装，但需要有效的染色体比对 和/或在有丝分裂和在一些非哺乳动物系统中的减数分裂期间分离。 我们将在雌性减数分裂期间专门干扰Kid或MCAK的功能 通过反义或显性负性构建体的转基因表达， 小鼠卵母细胞特异性启动子。我们将评估中断的后果 通过检测转基因小鼠的生育力， 雌性，转基因小鼠出生的幼崽的出生缺陷的频率和类型 雌性，以及来自雌性的卵母细胞减数分裂纺锤体上的染色体排列 转基因女性 这些实验的成功完成将验证 转基因小鼠技术，以研究纺锤体组装的机制， 哺乳动物的雌性减数分裂，并可能增加我们对病因学的理解 唐氏症之类的疾病吗s综合征。

DESCRIPTION (provided by applicant): It has been estimated that 15-20 percent of all human conceptions are chromosomally abnormal (aneuploid), and that many of these abnormalities occur because of errors in chromosome segregation during female meiosis. One of the strongest predictors of aneuploidy is maternal age with nearly half of all oocytes ovulated in women over age 40 containing errors in chromosome number. Most aneuploid conceptions die before birth, but several specific aneuploid states (e.g. trisomy 21) are viable and, as a class, represent the most common cause of mental retardation in man. Despite this clinical importance, very little is known about the cause of chromosome nondisjunction during female meiosis or why the rate of non-disjunction increases with maternal age. One model proposed to explain the correlation between maternal age and frequency of chromosome nondisjunction suggests that the efficiency of folliculogenesis (the development of the oocyte within the follicle in the ovary) is reduced in older women. We hypothesize that reduced or impaired folliculogenesis could contribute to chromosome non-disjunction by reducing the quantities of specific microtubule motor proteins necessary for alignment and/or segregation of chromosomes on the meiotic spindle. To test this hypothesis, we propose to use transgenic mouse technology to specifically perturb the function of the kinesin-related proteins Kid and MCAK during female meiosis. We are targeting Kid and MCAK because they are not necessary for overall spindle assembly, but are required for efficient chromosome alignment and/or segregation during mitosis and, in some non-mammalian systems, meiosis. We will specifically perturb the function of Kid or MCAK during female meiosis by transgenic expression of anti-sense or dominant negative constructs using a mouse oocyte-speciflc promoter. We will evaluate the consequences of disrupted motor function during female meiosis by examining the fertility of transgenic females, the frequency and type of birth defects in pups born from transgenic females, and the alignment of chromosomes on meiotic spindles in oocytes from transgenic females. Successful completion of these experiments will validate the application of transgenic mouse technology to study the mechanisms of spindle assembly during female meiosis in mammals and could increase our understanding of the etiology of disorders such as Down?s Syndrome.