Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Jun 6;69(3):139-146.
doi: 10.1262/jrd.2023-010. Epub 2023 Mar 17.

Cell cycle regulation for meiosis in mammalian germ cells

Ryuki Shimada  1 , Kei-Ichiro Ishiguro  1
Affiliations
Review

Cell cycle regulation for meiosis in mammalian germ cells

Ryuki Shimada et al. J Reprod Dev. .

Abstract

In mouse fetal gonads, germ cell development is accompanied by changes in cell cycle mode in response to external signals and intrinsic mechanisms of cells. During fetal development, male germ cells undergo G0/G1 arrest, while female germ cells exit the mitotic cell cycle and enter meiosis. In fetal testes, NANOS2 and CYP26B1 force germ cells to stay in G0/G1 arrest phase, preventing them from entering the meiotic cell cycle. In the fetal ovary, external signals, such as RA, BMP, and WNT, promote the competency of female germ cells to enter the meiotic cell cycle. MEIOSIN and STRA8 ensure the establishment of the meiotic cell cycle by activating meiotic genes, such that meiotic entry coincides with the S phase. This review discusses germ cell development from the viewpoint of cell cycle regulation and highlights the mechanism of the entry of germ cells into meiosis.

Keywords: Cell cycle; Germ cell; MEIOSIN; Meiosis; STRA8.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Fig. 1.
Fig. 1.
Cell cycle regulation associated with germ cell development. (A) Schematic illustration of the cell cycle events associated with germ cell development in the testis (upper right) and fetal ovary (lower right). The periods of key gene expressions (STRA8, MEIOSIN. CYP26B1, NANOS2) and extrinsic signal executions (RA, BMP, WNT) are shown along the developmental stages. In females, the meiotic cell cycle starts around E13.5-E14.5 and is followed by meiotic prophase and subsequently by dictyate/diplotene arrest. In fetal testis, meiotic entry is suppressed by CYP26B1 and NANOS2, leading to G0/G1 arrest of the germ cells. After birth, the meiotic cell cycle is accompanied by the differentiation of spermatocytes. (B) BMP signaling confers oogenic gene activation and the competency for meiosis to female germ cells. RA signaling is mediated by RARs (RARα, RARβ, RARγ) and retinoid X receptors (RXRs), which are bound by RA. RA signaling activates the meiotic program via the activation of the key genes for meiosis, such Stra8 and Rec8. (C) At E13.5 (upper), CYP26B1 degrades RA, preventing male germ cells from responding to RA. p38 MAPK signaling and NANOS2 suppress RA signaling in male germ cells. At E14.5 onward (lower), CYP26B1 expression decreases. Alternatively, NANOS2 inhibits mTORC1 activity via the suppression of Rheb. RB suppresses cell cycle progression. The attenuated pathways are shown in gray.
Fig. 2.
Fig. 2.
Schematic of meiotic cell cycle. (A) Meiosis comprises one round of DNA replication followed by two rounds of chromosome segregation. Meiosis starts from the pre-meiotic S phase followed by meiotic prophase I, which is equivalent to the G2 phase of the cell cycle. Meiosis-specific chromosome events occur during meiotic prophase I. Cohesin plays crucial roles in meiosis-specific chromosomal events during meiotic prophase I. In meiosis I, homologous chromosomes, rather than sister chromatids, are segregated in opposite directions. In meiosis II, sister chromatids are segregated. (B) Schematic illustrations of sequential chromosomal events during meiotic prophase. Pre-leptotene is the transition stage just before meiotic prophase I. Meiotic prophase I is divided into four substages according to chromosome morphology. During meiotic prophase I, sister chromatids are organized into the axial element (AE). Meiosis-specific cohesion is loaded onto the chromatin during leptotene. Homologous chromosomes undergo pairing and synapsis from leptotene to zygotene. The synaptonemal complex (SC) is fully assembled between homologous chromosomes at pachytene. Meiotic recombination generates crossovers between homologous chromosomes, yielding physical linkages called chiasmata. At diplotene, the SC is disassembled.
Fig. 3.
Fig. 3.
MEIOSIN and STRA8 direct meiotic initiation in germ cells. (A) STRA8 and MEIOSIN proteins are co-expressed in the pre-leptotene spermatocyte in the seminiferous stages VII-VIII. STRA8 is also expressed in the spermatogonium that is negative for MEIOSIN. Enlarged images are shown on the right. Pre-lep. Sp.: Pre-leptotene spermatocyte. Round Sp.: Round spermatid. Spg.: Spermatogonium. Scale bar: 25 μm. (B) Embryonic (E14.5) ovary section was stained as in (A). STRA8 and MEIOSIN proteins are co-expressed in the pre-leptotene germ cells. Scale bar: 25 μm. The samples were prepared and the images were acquired as described previously [68]. (C) Schematic illustration of sequential activation of meiotic prophase genes. Meiotic genes were primed before meiotic entry. BMP signaling also contributes to transcriptional priming, at least in females. MEIOSIN and STRA8 amplify meiotic gene transcription.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Ginsburg M, Snow MH, McLaren A. Primordial germ cells in the mouse embryo during gastrulation. Development 1990; 110: 521–528. - PubMed
    1. Tam PP, Snow MH. Proliferation and migration of primordial germ cells during compensatory growth in mouse embryos. J Embryol Exp Morphol 1981; 64: 133–147. - PubMed
    1. Saitou M, Yamaji M. Primordial germ cells in mice. Cold Spring Harb Perspect Biol 2012; 4: a008375. - PMC - PubMed
    1. Koubova J, Menke DB, Zhou Q, Capel B, Griswold MD, Page DC. Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc Natl Acad Sci USA 2006; 103: 2474–2479. - PMC - PubMed
    1. Bowles J, Knight D, Smith C, Wilhelm D, Richman J, Mamiya S, Yashiro K, Chawengsaksophak K, Wilson MJ, Rossant J, Hamada H, Koopman P. Retinoid signaling determines germ cell fate in mice. Science 2006; 312: 596–600. - PubMed