Germ cell fate decisions are poorly understood, despite their central role in reproduction. One fundamental question has been whether germ cells are regulated to enter the meiotic cell cycle (i.e., mitosis-meiosis decision) and to be sperm or oocyte (i.e., sperm-oocyte decision) through one or two cell fate choices. If a single decision is used, a male-specific or female-specific meiotic entry would lead necessarily toward spermatogenesis or oogenesis, respectively. If two distinct decisions are used, meiotic entry should be separable from specification as sperm or oocyte. Here, we investigate the relationship of these two decisions with tools uniquely available in the nematode Caenorhabditis elegans. Specifically, we used a temperature-sensitive Notch allele to drive germ-line stem cells into the meiotic cell cycle, followed by chemical inhibition of the Ras/ERK pathway to reprogram the sperm-oocyte decision. We found that germ cells already in meiotic prophase can nonetheless be sexually transformed from a spermatogenic to an oogenic fate. This finding cleanly uncouples the mitosis-meiosis decision from the sperm-oocyte decision. In addition, we show that chemical reprogramming occurs in a germ-line region where germ cells normally transition from the mitotic to the meiotic cell cycle and that it dramatically changes the abundance of key sperm-oocyte fate regulators in meiotic germ cells. We conclude that the C. elegans mitosis-meiosis and sperm-oocyte decisions are separable regulatory events and suggest that this fundamental conclusion will hold true for germ cells throughout the animal kingdom.
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"After acquiring competency for gametogenesis, germ cells are ready for adopting several gametogenic pathways including mitosis/meiosis decision, establishment of germline stem cells, and sperm–egg fate decision. In C. elegans, sperm–egg and mitosis–meiosis fate decisions are separable pathways . In mice, the disruption of Stra8 blocks meiotic entry, but oocyte differentiation and growth occur . "
[Show abstract][Hide abstract]ABSTRACT: Germ cells are the common cells of origin for both types of two different gametes: sperm and eggs. In vertebrates so far examined, the sex of germ cells is determined by gonadal somatic cells. However, influenced by the somatic cells, how germ cells adopt their sexual fates by intrinsic factors has long been unclear in vertebrates. We recently identified forkhead box L3 (Foxl3) as a germ cell-intrinsic factor involved in the sperm-egg fate decision in the teleost fish, medaka (Oryzias latipes). On the basis of the results obtained by the analysis offoxl3/Foxl3 expression and loss-of-function mutants, we review when and how germ cell sex is regulated non-cell autonomously and cell-autonomously. We then discuss that the germline sex determination pathway is genetically distinct from other essential gametogenic pathways such as meiotic entry and the establishment of germline stem cells. Another extraordinary finding in thefoxl3mutant is that functional sperm can be produced in the ovary, which provides a new notion that gametogenesis can proceed irrespective of the sex of the surrounding somatic cells once the sexual identity of germ cells is established in medaka.
Preview · Article · Mar 2016 · Biology of Reproduction
"In C. elegans, these decisions have now been separated definitively: using genetic and chemical tools to manipulate these decisions separately, germ cells initially fated to become sperm can be induced to switch to an oocyte fate even after meiotic entry has occurred (Morgan et al., 2013). Nonetheless, C. elegans GSC progeny progress towards both decisions at about the same time, and the regulatory networks driving the two decisions overlap (Kimble and Crittenden, 2007; Morgan et al., 2013). Thus, the two decisions are separate but linked. "
[Show abstract][Hide abstract]ABSTRACT: C. elegans germline stem cells are a particularly simple system for analysis of stem cell regulation. Their well-defined mesenchymal niche consists of a single cell, the Distal Tip Cell, which uses Notch signaling to maintain a pool of germline stem cells. Downstream of Notch signaling a post-transcriptional regulatory network dictates self-renewal or differentiation. The major self-renewal hub of that network is FBF, a conserved RNA-binding protein and conserved stem cell regulator. FBF represses mRNAs encoding key regulators of germline differentiation (entry into the meiotic cell cycle, sperm or oocyte specification) as well as established regulators of somatic differentiation. Transcriptional and post-transcriptional mechanisms also control totipotency in the C. elegans germline. The key C. elegans GSC regulators are conserved broadly, making this system a paradigm for stem cell regulation.
[Show abstract][Hide abstract]ABSTRACT: Oogenesis is the process by which ovarian germ cells undertake meiosis and differentiate to become eggs. In mice, Stra8 is required for the chromosomal events of meiosis to occur, but its role in differentiation remains unknown. Here we report Stra8-deficient ovarian germ cells that grow and differentiate into oocyte-like cells that synthesize zonae pellucidae, organize surrounding somatic cells into follicles, are ovulated in response to hormonal stimulation, undergo asymmetric cell division to produce a polar body and cleave to form two-cell embryos upon fertilization. These events occur without premeiotic chromosomal replication, sister chromatid cohesion, synapsis or recombination. Thus, oocyte growth and differentiation are genetically dissociable from the chromosomal events of meiosis. These findings open to study the independent contributions of meiosis and oocyte differentiation to the making of a functional egg.