Meiotic spindle formation in Drosophila females

描述（由申请人提供）：在第一次减数分裂期间，通过交叉连接的同源染色体与纺锤体微管相互作用并分离到相反的两极。这一过程中的缺陷导致受精卵的非整倍体，并对发育产生严重后果，通常导致发育中的胚胎死亡。在人类中，非整倍体是妇女自然流产和不孕的主要原因。如果非整倍体确实存活下来，它们会表现出唐氏综合征、特纳综合征或克氏综合征等疾病。在许多生物中，包括人类和苍蝇，卵母细胞减数分裂纺锤体缺乏中心粒和典型的微管组织中心在两极。由于中心体和它们的组成蛋白通常组织双极纺锤体，所以卵母细胞减数分裂中的纺锤体极组织必须通过另一种机制发生。果蝇卵母细胞是研究无中心体纺锤体形成机制的理想系统。Subito是人类有丝分裂驱动蛋白样蛋白2（MKLP 2）的果蝇同源物，是雌性减数分裂期间双极纺锤体形成所必需的。Subito是减数分裂中期纺锤体发育所必需的，这种结构可能是在没有中心体的情况下形成双极纺锤体的关键。本研究的目的是：（1）分析Subito的结构和功能。这将为了解这种蛋白质的功能和调节方式提供见解。ii）表征Subito和Passenger蛋白或Ran途径之间的相互作用。这将确定哪些蛋白质与Subito相互作用以及它们在纺锤体组装中的功能。iii）确定双极纺锤体形成和染色体定向的时间。这将测试极间微管和动粒微管的相对重要性，并研究同源染色体对如何在无中心体纺锤体上定向。iv）分析减数分裂纺锤体组装所需的新基因。这将确定新的基因所需的acentrosomal纺锤体组装使用一个相对公正的方法。在第一次减数分裂期间，染色体数目减少一半，将成对的同源染色体分离到配子中。在人类中，减数分裂的错误导致非整倍体，精子或卵子中染色体数量异常，并且是自然流产、妇女不孕症和唐氏综合征、特纳综合征或克氏综合征等疾病的主要原因。这些研究的目的是了解这些错误是如何发生的。

DESCRIPTION (provided by applicant): During the first meiotic division, homologous chromosomes linked by chiasmata interact with the spindle microtubules and segregate to opposite poles. Defects in this process lead to aneuploidy in the fertilized egg and have serious consequences on development, often resulting in death of the developing embryo. In humans, aneuploidy is a leading cause of spontaneous abortions and infertility in women. If aneuploids do survive, they manifest with diseases such as Down's, Turner's or Klinefelter's syndrome. In many organisms, including humans and flies, the oocyte meiotic spindle lacks centrioles and the classical microtubule-organizing center at the poles. Since the centrosomes and their constituent proteins usually organize bipolar spindles, spindle pole organization in oocyte meiosis must occur by another mechanism. Drosophila melanogaster oocytes are an excellent system to elucidate the mechanisms of acentrosomal spindle formation. Subito is the Drosophila homolog of human Mitotic Kinesin Like Protein 2 (MKLP2) and is required for bipolar spindle formation during female meiosis. Subito is required for the development of the central spindle at meiotic metaphase and this structure may be critical for formation of a bipolar spindle in the absence of centrosomes. The goals of this study are: i) analyze the structure and function of Subito. This will provide insights into how this protein functions and is regulated. ii) characterize the interactions between Subito and the Passenger proteins or the Ran pathway. This will determine which proteins interact with Subito and what is their function in spindle assembly. iii) determine the timing of bipolar spindle formation and chromosomes orientation. This will test the relative importance of interpolar and kinetochore microtubules and investigate how pairs of homologous chromosomes orient on the acentrosomal spindle. iv) analyze new genes required for meiotic spindle assembly. This will identify new genes required for acentrosomal spindle assembly using a relatively unbiased approach. During the first meiotic division, the chromosome number is reduced in half by separating pairs of homologous chromosomes into the gametes. In humans, errors in meiosis lead to aneuploidy, an abnormal number of chromosomes in a sperm or egg, and is the leading cause of spontaneous abortions, infertility in women and diseases such as Down's, Turner's or Klinefelter's syndrome. The objective of these studies is to understand how these errors occur.