Exposing the mechanisms underlying mammalian meiotic onset (2016–2018)
Meiosis is a unique and highly specialised form of cell division, critical to the survival of the species. Understanding the details of how meiosis is initiated and how it progresses is a fundamental problem of cell biology but also of considerable relevance to medicine. In mammals the first step of meiosis is triggered at a single time-point in germ cells of the fetal ovary whereas, in males, meiosis is initiated at puberty and then repeatedly throughout adult life. We aim to reveal the details of meiotic initiation and to uncover roles for novel components of early meiotic progression using the mouse as a model organism. Within this project we will apply skills in reproductive biology, developmental biology, molecular genetics and mouse manipulation. Specifically, we will: 1. Determine how the homeodomain transcription factor Cdx2 comes to be expressed in pre-meiotic germ cells of the fetal ovary and determine its function in meiotic onset and progression by deleting the gene specifically in developing germ cells; 2. Determine how the meiotic ¿¿¿gatekeeper¿¿¿, Stra8, is regulated in fetal ovary and pubertal testis using cell culture assays and mutant mouse lines in which putative regulatory elements are modified by Crispr/Cas9 targeting; and 3. Compare the transcriptomes of fetal ovarian germ cells just before and after Stra8 expression and determine the role of the transcription factor, Sox30, in meiotic progression in both sexes by analysing a germ cell specific knockout line. We aim to expose new knowledge of relevance to our understanding of normal germ cell development and fertility/infertility in both sexes. In addition, we anticipate that outcomes of this research will inform and contribute to the ongoing goals of enhancing fertility (e.g. generating human gametes in vitro) or controlling fertility (e.g. development of a male contraceptive).