Molecular regulation of the mitosis/meiosis decision in multicellular organisms

Abstract

A major step in the journey from germline stem cell to differentiated gamete is the decision to leave the mitotic cell cycle and begin progression through the meiotic cell cycle. Over the past decade, molecular regulators of the mitosis/meiosis decision have been discovered in most of the major model multicellular organisms. Historically, the mitosis/meiosis decision has been closely linked with controls of germline self-renewal and the sperm/egg decision, especially in nematodes and mice. Molecular explanations of those linkages clarify our understanding of this fundamental germ cell decision, and unifying themes have begun to emerge. Although the complete circuitry of the decision is not known in any organism, the recent advances promise to impact key issues in human reproduction and agriculture.

Figure 1.

Universal features of mitotic and meiotic germ cell cycles. Mitotic divisions duplicate diploid germ cells (yellow cells, 2 depicts diploidy), whereas meiotic divisions generate haploid germ cells (green cells, 1 depicts haploidy). The red arrow shows that the decision to leave the mitotic cell cycle and enter the meiotic cell cycle occurs prior to meiotic S-phase. Meiotic prophase I progresses from its earliest stages (crescent depicts chromosomal bouquet), through pachytene (wavy lines depict synapsed chromosomes), to later stages (chromosomal bivalents) that line up at the metaphase plate at meiosis division I.

Figure 2.

The C. elegans mitosis/meiosis decision. (A) The nematode germline possesses a GSC pool within its somatic niche. Germ cells in the mitotic cell cycle (yellow) extend beyond the niche and include transit-amplifying (TA) germ cells, which have been triggered to begin maturation toward meiotic entry (green arrow); germ cells in the meiotic cell cycle (green) are more proximal. Overt entry into the meiotic cell cycle (red arrow) occurs asynchronously. Conventions are as in Figure 1. (B) Molecular regulation of the C. elegans mitosis/meiosis decision includes Notch signaling from the niche and FBF maintenance of GSCs, including repression of the meiotic program. Arrows indicate positive regulation; barred lines indicate negative regulation. Solid arrows and lines indicate direct molecular regulation: Notch signaling directly activates fbf-2 transcription and FBF directly represses mRNAs of the meiotic program as well as key differentiation regulators.

Figure 3.

The Drosophila mitosis/meiosis decision. (A) The Drosophila germline possesses asymmetrically dividing GSCs within its somatic niche; transit-amplifying divisions form a 16-cell cyst and meiotic entry (red arrow) occurs in that 16-cell cyst. In males, all 16 germ cells enter the meiotic cell cycle, as depicted here; in females, only two of the 16 germ cells enter the meiotic cell cycle (not shown). Conventions and acronyms are as in Figures 1 and 2. (B) Molecular regulation of the Drosophila mitosis/meiosis decision relies on extrinsic BMP signaling and intrinsic Bam/bgcn RNA regulation, with abundant Bam controlling the position of meiotic entry. Solid arrows and lines indicate direct molecular regulation; dashed line indicates control that may be either direct or indirect.

Figure 4.

The mouse mitosis/meiosis decision. (A) Meiotic entry (red arrow) occurs during fetal development in female mice and after puberty in males. PGCs (yellow) enter the fetal somatic gonad, which is sexually bipotential (purple). Sex determination of the fetal somatic gonad results in a female (rose) or male (blue) somatic gonad; in these fetal developing gonads, female PGCs enter the meiotic cell cycle (green), whereas male PGCs arrest in the mitotic cell cycle (yellow). After puberty, female germ cells produce mature oocytes, whereas the male maintain spermatogonial stem cells (yellow), transit-amplifying cells (yellow) and meiotic cells (green) that produce mature sperm. No individual cross-section of the seminiferous tubule (dotted line) has all stages because of the wave of maturation along its length. (B) Molecular regulation of the murine mitosis/meiosis decision. Retinoic acid activates expression of STRA8, which governs meiotic entry by an unknown mechanism. NOS2 has been implicated in repression of the stra8 mRNA as well as mRNAs encoding the meiotic machinery. In the male fetal gonad, Cyp26b1 inhibits retinoic acid and blocks meiotic entry. Solid arrows and lines indicate direct molecular regulation; dashed line indicates control that may be either direct or indirect.