Evidence for intercellular bridges and radial patterning of meiotic initiation in the human fetal ovary

Meiosis is the hallmark of reproduction. Our understanding of early oocyte development was improved by studying the spatiotemporal dynamics and mechanisms governing meiosis in mice, however, our knowledge of the meiotic initiation process in humans remains limited. Here, we utilized three-dimensional (3D) analysis to determine spatiotemporal dynamics of meiotic initiation in fetal human ovaries. Similar to mice, we found that the first meiotic cells appear in clusters in the center of human fetal ovaries as early at 9 weeks and that the initiation of meiosis propagates as a radial wave. Between developing germ cells in fetal human ovaries, we detected a component of the intercellular bridge, TEX14 protein. 3D quantification of germ cells in ovaries collected at the end of first trimester revealed, for the first time, considerable variation in the number of meiotic cells between individuals and asynchronous mitotic-meiotic transition. In addition to illustrating the geography of meiotic initiation in ovaries from the first trimester, we extended our 3D analysis approach to second trimester and showed heterogeneous spatial distribution of meiotic and non-meiotic germ cells in human fetal ovaries. This study is an important step towards better understanding of 3D structure of developing ovary and early stages of meiosis in humans. Highlights - Organic solvent-based clearing methods and confocal microscopy can be implemented to visualize and quantify germ cells in the intact human fetal ovary. - Identification of a new, radial, pattern of meiotic initiation in the ovaries from the first trimester. - Immunolocalization of the intercellular bridge component TEX14 between developing germ cells in the fetal ovary - Maintenance of pre-meiotic germ cells in second trimester ovaries suggests less synchronous mitotic-meiotic stage transition.