Meiotic spindle formation in Drosophila females

描述（由申请人提供）：在第一次减数分裂中，由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。这个过程中的缺陷会导致受精卵的非整倍性，并对发育产生严重后果，经常导致发育中的胚胎死亡。在人类中，非整倍体是女性自然流产和不孕的主要原因。如果非整倍体存活下来，它们会表现为唐氏综合症、特纳氏综合症或克兰费尔特综合症等疾病。在包括人类和苍蝇在内的许多生物中，卵母细胞减数分裂纺锤体在两极缺乏中心粒和经典的微管组织中心。由于中心体及其组成蛋白通常组织双极纺锤体，因此卵母细胞减数分裂中纺锤体极的组织必须通过另一种机制进行。黑腹果蝇卵母细胞是阐明无丝胞体纺锤体形成机制的一个很好的系统。Subito是人类有丝分裂运动蛋白样蛋白2 （MKLP2）的果蝇同源基因，是雌性减数分裂过程中双极纺锤体形成所必需的。在减数分裂中期，中心纺锤体的发育是必需的，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。这将使我们深入了解这种蛋白质的功能和调控机制。ii)描述Subito与客运蛋白或Ran途径之间的相互作用。这将决定哪些蛋白质与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方向的时间。这将测试极间微管和着丝点微管的相对重要性，并研究同源染色体对如何在无丝体纺锤体上定向。Iv)分析减数分裂纺锤体组装所需的新基因。这将用一种相对公正的方法鉴定出无丝胞体纺锤体组装所需的新基因。在第一次减数分裂中，染色体数目通过将同源染色体对分离到配子中而减少一半。在人类中，减数分裂的错误会导致非整倍体，即精子或卵子中的染色体数量异常，这是自然流产、女性不孕以及唐氏症、特纳氏症或克兰费尔特综合症等疾病的主要原因。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.