During the first meiotic division, homologous chromosomes linked by chiasmata interact with spindle microtubules and segregate to opposite poles. Defects in this process lead to aneuploidy in the fertilized egg and usually in death of the developing embryo. In humans, aneuploidy is a leading cause of spontaneous abortions and infertility in women and causes diseases such as Down, Turner or Klinefelter syndromes. In many organisms, including mammals and insects, the oocyte meiotic spindle lacks centrosomes. In the absence of the microtubule-organizing center found at mitotic spindle poles, the chromosomes generate a signal which stimulates spindle assembly. In cells with centrosomes, the microtubule connections formed between the poles and the kinetochores facilitates bi-orientation of sisters (mitosis) or homologous chromosomes (meiosis I). In acentrosomal cells, novel mechanisms may be employed to bi-orient the homologs. We have found that a group of central spindle proteins, including the Chromosome Passenger Complex (CPC) is critical for formation of a bipolar spindle and orientation of the homologs. These proteins recruit and organize the antiparallel microtubules overlap in the center of the spindle. How these microtubules mediate chromosome behavior is not known. In this proposal, we will investigate the mechanisms of homolog orientation in the acentrosomal spindle of Drosophila oocytes. The CPC is recruited to chromosomes even in the absence of microtubules but unlike mitotic cells, CPC proteins are not found at the centromeres. Instead, the CPC is found in a ring around the chromosomes where it recruits factors which regulate spindle assembly such as Subito. The ring structure also provides a mechanism for directing spindle bipolarity in the absence of centrosomes. To investigate the role of the central spindle in homolog orientation, we will use fluorescently tagged proteins and live imaging to investigate the timing of homolog orientation relative to spindle assembly and establishment of the central spindle. We will also determine the role of kinetochores in chromosome alignment and segregation. Since these genes are essential, we will use sophisticated genetic tools available in Drosophila to generate oocytes lacking these proteins. This includes newly developed germ line RNAi and germ line clones to test the role of different kinetochore components. Finally, we will test the hypothesis that the bi-orientation of homologs depends on an interaction between chromosome associated and central spindle microtubules.

Public Health Relevance

Aneuploidy, or an abnormal chromosome number, is a leading cause of spontaneous abortions and infertility in women and also causes diseases such as Down, Turner or Klinefelter syndromes. The object of this research is to understand how oocytes receive the correct number of chromosomes and the mechanisms of the errors that lead to errors in this process.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
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Deatherage, James F
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Rutgers University
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New Brunswick
United States
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Das, Arunika; Cesario, Jeffry; Hinman, Anna Maria et al. (2018) Kinesin 6 Regulation in Drosophila Female Meiosis by the Non-conserved N- and C- Terminal Domains. G3 (Bethesda) 8:1555-1569
Radford, Sarah J; Nguyen, Alexandra L; Schindler, Karen et al. (2017) The chromosomal basis of meiotic acentrosomal spindle assembly and function in oocytes. Chromosoma 126:351-364
Radford, Sarah J; Go, Allysa Marie M; McKim, Kim S (2017) Cooperation Between Kinesin Motors Promotes Spindle Symmetry and Chromosome Organization in Oocytes. Genetics 205:517-527
Radford, Sarah J; McKim, Kim S (2016) Techniques for Imaging Prometaphase and Metaphase of Meiosis I in Fixed Drosophila Oocytes. J Vis Exp :
Gyuricza, Mercedes R; Manheimer, Kathryn B; Apte, Vandana et al. (2016) Dynamic and Stable Cohesins Regulate Synaptonemal Complex Assembly and Chromosome Segregation. Curr Biol 26:1688-1698
Das, Arunika; Shah, Shital J; Fan, Bensen et al. (2016) Spindle Assembly and Chromosome Segregation Requires Central Spindle Proteins in Drosophila Oocytes. Genetics 202:61-75
Radford, Sarah J; Hoang, Tranchau L; G?uszek, A Agata et al. (2015) Lateral and End-On Kinetochore Attachments Are Coordinated to Achieve Bi-orientation in Drosophila Oocytes. PLoS Genet 11:e1005605
Mathieu, Juliette; Cauvin, Clothilde; Moch, Clara et al. (2013) Aurora B and cyclin B have opposite effects on the timing of cytokinesis abscission in Drosophila germ cells and in vertebrate somatic cells. Dev Cell 26:250-65