Identification of Novel Regulators of Entry into the Meiotic Program
Final Report Abstract
This one-year OFFSPRing pilot project was funded as part of the “DFG nachwuchsakademie” in the field of Reproductive Medicine and Biology. The project focussed on the entry of germ cells into meiosis, a vital step in the production of healthy eggs and sperm during reproduction. The central questions of the pilot project were; how do somatic, mitotically dividing early germ cells enter meiosis and become haploid germ cells? How do cells switch from mitotic division to meiotic division, and how are meiotic cell divisions prevented in mitotically dividing cells? Only very few factors that control the fundamental cell fate switch from mitosis to meiosis are known, despite the obvious importance for all higher eukaryotic life. The lack of knowledge in this area is in part due to difficulty in identifying cells that have just entered the meiotic program. To overcome this problem, we used a meiotic reporter gene in combination with a high throughput genome-wide knockdown screen in ES cells. This approach allowed us to identify 279 candidates that may potentially be involved in the entry of germ cells into meiosis. Using several methods, including bioinformatic expression analysis available from both published and unpublished datasets, we have been able to assess the quality of the candidates and their likelihood of being key players in the meiotic cell cycle switch. This has allowed us to arrive at a Top 30 hit list, which contains genes where we have good evidence of their involvement in meiotic-entry. Our preliminary results, where we have begun to closely examine the Top 30 hits, has revealed a small number of very promising hits, which we now plan to thoroughly investigate with the creation of an inducible knock-out mouse model to fully understand the in vivo role of these promising meiotic entry candidate genes. The identification of one or more key mammalian regulators of entry into meiosis will have a profound impact on the areas of germ cell research, reproductive biology and medicine as they address a very fundamental process: the distinction between mitotic and meiotic cell division. Our findings should also benefit the area of cancer biology and oncology, since the aberrant expression of meiotic genes has been reported in several human tumours and suggested to causatively contribute to tumour cell survival and increasing aggressiveness.
