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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067142-07
Application #
7680220
Study Section
Special Emphasis Panel (ZRG1-BDA-L (02))
Program Officer
Deatherage, James F
Project Start
2003-01-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
7
Fiscal Year
2009
Total Cost
$303,246
Indirect Cost
Name
Rutgers University
Department
Type
Organized Research Units
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Radford, Sarah J; Jang, Janet K; McKim, Kim S (2012) The chromosomal passenger complex is required for meiotic acentrosomal spindle assembly and chromosome biorientation. Genetics 192:417-29
Radford, Sarah J; Harrison, Andrew M; McKim, Kim S (2012) Microtubule-depolymerizing kinesin KLP10A restricts the length of the acentrosomal meiotic spindle in Drosophila females. Genetics 192:431-40
Cesario, J; McKim, K S (2011) RanGTP is required for meiotic spindle organization and the initiation of embryonic development in Drosophila. J Cell Sci 124:3797-810
McKim, Kim S; Joyce, Eric F; Jang, Janet K (2009) Cytological analysis of meiosis in fixed Drosophila ovaries. Methods Mol Biol 558:197-216
Wu, Changjian; Singaram, Vinod; McKim, Kim S (2008) mei-38 is required for chromosome segregation during meiosis in Drosophila females. Genetics 180:61-72
Colombie, Nathalie; Cullen, C Fiona; Brittle, Amy L et al. (2008) Dual roles of Incenp crucial to the assembly of the acentrosomal metaphase spindle in female meiosis. Development 135:3239-46
Jang, Janet K; Rahman, Taslima; Kober, Vanessa S et al. (2007) Misregulation of the kinesin-like protein Subito induces meiotic spindle formation in the absence of chromosomes and centrosomes. Genetics 177:267-80
Doubilet, Susan; McKim, Kim S (2007) Spindle assembly in the oocytes of mouse and Drosophila--similar solutions to a problem. Chromosome Res 15:681-96
Cesario, Jeff M; Jang, Janet K; Redding, Bethany et al. (2006) Kinesin 6 family member Subito participates in mitotic spindle assembly and interacts with mitotic regulators. J Cell Sci 119:4770-80
Horner, Vanessa L; Czank, Andreas; Jang, Janet K et al. (2006) The Drosophila calcipressin sarah is required for several aspects of egg activation. Curr Biol 16:1441-6

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