Research Summary

The research of the Laboratory of Biochemistry and Molecular Biology of Germ Cells is focused on the study of the mechanisms regulating the progression of mammalian oocytes through meiotic division, and on the molecular basis of the main morphological changes occurring during this process (nuclear envelope breakdown, formation of the spindle, chromosome condensation and segregation). Gametogenesis and fertilization are the key events in sexual reproduction. In the female, meiosis results in a large oocyte that is competent for fertilization and fundamental for the success of early embryonic development. One of the major problems occurring during mammalian meiosis is the high incidence of errors, leading to chromosomal aberrations, which are more prevalent in female gametes and seem to increase with maternal age. Oocyte aneuploidy has severe consequences including pregnancy loss or birth defects. Aneuploidy is believed to be a two-step process; initially an error occurs in the early meiotic program during recombination, which is then followed by a failure of the mechanisms controlling the chromosome segregation during the resumption of meiosis. To address the above issues, we currently concentrate on two major areas of research, which are studied in our laboratory:

Intracellular Venues of mRNA translation

A characteristic of early development in mammals is the reliance on the translation and utilization of stored RNAs and proteins rather than de novo transcription of genes in order to sustain rapid development. After a period of active transcription during growth, the nucleus of mammalian oocytes becomes transcriptionally inactive. Post-transcriptional control of gene expression at the level of translation has emerged as an important cellular function in normal development. In the absence of transcription, the completion of meiosis and early embryo development in mammals relies significantly on maternally synthesized RNAs. Therefore, the regulation of gene expression in oocytes is controlled almost exclusively at the level of mRNA stabilization and translation.
We discovered that the RNA distribution in this large cell type indicates a novel set of regulatory mechanisms needed to ensure specific gene expression at the right time and place. Spatial translational control may provide an important means to maintain and refine patterns of expression during the dynamic onset of meiosis.  Indeed, the distribution of certain transcripts and proteins appears to be distinct. This contributes to spindle and chromosome organization and thus plays an important role in the maintenance of genomic stability. Major causes of human aneuploidy involve errors that arise during meiosis. Our research suggest that mislocalization of specific transcripts within the oocyte and their aberrant translation could be another cause of aneuploidy. Our studies also suggest a spatio-temporally regulated translational control of chromosome segregation and formation of the functional spindle mediated by a mTOR/4F pathway during the meiotic progression of mammalian oocytes. Our projects investigate the translational components that are potential clinically relevant targets for the development of a healthy oocyte that sustains embryo development.

                             (1) Translational activity (red) in the oocyte