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.
|Effective start/end date||1/1/03 → 8/31/13|
- National Institutes of Health (NIH)