Attila Toth

Mammalian meiosis

Previous and current research

The main interest of the lab is meiosis in mammals (figure 1). Meiosis and gametogenesis are among the most ancient developmental processes widespread among eukaryotes. By generating haploid gametes from diploid mother-cells, meiosis forms the basis of sexual reproduction.

Fig 1  Moues oocyte during the first meiotic metaphase. Chromosomes (blue) align on the metaphase spindle, stained by antibodies recognising tubulin (green).

Research on meiosis has very important implications. Errors in meiosis can result in an abnormal number of chromosomes, or aneuploidy. Aneuploidy leads to clinical conditions such as pregnancy loss, Down Syndrome, and poor oocyte quality and infertility. In fact, an increase in the frequency of meiotic chromosome segregation defects is one of the key factors responsible for decline in female fertility during aging.
Our goal is to understand the mechanisms that distinguish meiosis from mitosis and enable the generation of haploid gametes. The other main focus of the lab is development of methods for the induction of meiosis in vitro in stem cell culture. To achieve these goals, we want to identify and characterise novel meiotic genes, focusing on genes that are specifically involved in meiotic chromosome segregation and chromosome behaviour in mice.
Recently we have started a functional genomic screen to identify murine genes specifically involved in meiosis. Using microarray analysis we have identified genes that are preferentially expressed during meiosis in both sexes and therefore likely to be involved in core meiotic processes such as meiotic chromosome segregation. To study chromosome behaviour in mice, we generated a transgenic mice-strain that expresses a GFP tagged version of the meiosis specific cohesion protein Rec8 under its own promoter (figure 2.).

Fig2. Section of the testis from an adult Rec8-GFP transgenic mouse. Rec8-GFP is specifically expressed in meiotic germ cells and localises to the core of chromosomes in pachytene cells.

Currently we are in the process of analysing meiotic genes identified by the screen, which involves generation of antibodies to candidates, interfering with the function of candidates by RNAi and generation of mice knock outs.

Future prospects and goals

• Study in detail the identified meiosis specific genes in order to better understand the molecular mechanisms underlying the generation of haploid gametes in mammals.
• Expanding our functional genomic screen to identify genes involved in aspects of meiosis that has not been examined by our screen up till now.
• Development of strategies and procedures for in vitro induction of meiosis in stem cells.
  

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Selected publications

Wojtasz, L., Daniel, K., Roig, I., Bolcun-Filas, E., Xu, H., Boonsanay, V., Eckmann, C.R., Cooke, H.J., Jasin, M., Keeney, S., McKay, M.J., Tóth, A. (2009) Mouse HORMAD1 and HORMAD2, two conserved meiotic chromosomal proteins, are depleted from synapsed chromosome axes with the help of TRIP13 AAA-ATPase. PLoS Genet. 2009 Oct;5(10):e1000702. Epub 2009 Oct 23.

Fukuda, T., Daniel, K., Wojtasz, L., Tóth, A., Höög, C. (2009). A novel mammalian HORMA domain-containing protein, HORMAD1, preferentially associates with unsynapsed meiotic chromosomes. Exp Cell Res. 2009 Aug 15. [Epub ahead of print]

Wojtasz, L., Daniel, K., Tóth, A. (2009). Fluorescence Activated Cell Sorting of Live Female Germ Cells and Somatic Cells of the Mouse Fetal Gonad Based on Forward and Side Scattering. Cytometry Part A 75A:547-53.

Rabitsch, K.P.*, Tóth, A.*, Gálová, M., Schleiffer, A., Schaffner, G., Aigner, E., Rupp, C., Penkner, A.M., Moreno-Borchart, A.C., Primig, M., Esposito, R.E., Klein, F., Knop, M., Nasmyth, K. (2001). A screen for genes required for meiosis and spore formation based on whole-genome expression. Curr. Biol. 11, 1001-9.          
*These authors contributed equally to this work

Tóth, A.*, Rabitsch, K.P.*, Gálová, M., Schleiffer, A., Buonomo, S.B.C., Nasmyth, K. (2000). Functional genomics identifies monopolin: a kinetochore protein required for segregation of homologues during meiosis I. Cell 103, 1155-68.
*These authors contributed equally to this work

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