How is meiosis initiated in the mouse fetal ovary?

CA Feng1,2, T Davidson2, PA Koopman2 and J Bowles1,2

  1. School of Biomedical Sciences, The University of Queensland, Brisbane, Australia
  2. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia

There is a population of cells in the gonads called the germ cells that are the precursors of spermatids and oocytes and, as such, they possess the unique ability to undergo meiotic cell division in order to generate these haploid gametes. In mammals, a factor critical for the initiation of meiotic entry is Stimulated by Retinoic Acid gene 8 (STRA8) and, as the name suggests, retinoic acid (RA) is a known regulator of the associated gene. It is now well-accepted that RA is required for Stra8 expression in the post-natal testis and substantial evidence exists that, during fetal ovarian development, RA induces germ cells to express Stra8. Nonetheless, the role of RA in the fetal ovary has been disputed principally because some germ cells in embryos lacking two major RA-synthesising enzymes, ALDH1A2 and ALDH1A3, remain able to enter meiosis. Another major factor casting doubt over the involvement of RA in the fetal ovaries is that studies utilizing Stra8 promoters containing putative RA responsive elements are only capable of driving transgene expression in the post-natal testis and not fetal ovaries. New evidence for the role of RA in initiating Stra8 expression will be presented. We have also studied the specific molecular mechanisms involved in the onset of Stra8 expression focusing on a previously unexamined region of the Stra8 promoter and identified candidate regulatory elements using in vitro assays. Going further we have confirmed the function of the identified element(s) in regulating ovarian meiosis through direct genome editing of the genomic Stra8 promoter using CRISPR/Cas9 technology in mice.