Modulation of cell cycle control during oocyte-to-embryo transitions

Abstract

Ex ovo omnia--all animals come from eggs--this statement made in 1651 by the English physician William Harvey marks a seminal break with the doctrine that all essential characteristics of offspring are contributed by their fathers, while mothers contribute only a material substrate. More than 360 years later, we now have a comprehensive understanding of how haploid gametes are generated during meiosis to allow the formation of diploid offspring when sperm and egg cells fuse. In most species, immature oocytes are arrested in prophase I and this arrest is maintained for few days (fruit flies) or for decades (humans). After completion of the first meiotic division, most vertebrate eggs arrest again at metaphase of meiosis II. Upon fertilization, this second meiotic arrest point is released and embryos enter highly specialized early embryonic divisions. In this review, we discuss how the standard somatic cell cycle is modulated to meet the specific requirements of different developmental stages. Specifically, we focus on cell cycle regulation in mature vertebrate eggs arrested at metaphase II (MII-arrest), the first mitotic cell cycle, and early embryonic divisions.

Figure 1

Schematic representation of cell cycle regulation during Xenopus early development. Illustrated are specialized cell cycle types, major developmental transitions and oocyte/embryo stages, as well as oscillations of Cdk1–cyclin B and APC/C activity. Bars in the lower half depict activity levels for XErp1/Emi2, c-Mos/MAPK, Emi1 and the spindle assembly checkpoint (SAC), as well as inhibitory Thr-14/Tyr-15 phosphorylation of Cdk1 (Cdk1-pY). See text for details.

Figure 2

Cdk1 regulatory mechanisms. Red background colour indicates inactive Cdk1 or inhibitory phosphorylation (P), while green colour denotes active Cdk1 or activating phosphorylation. CycB and Cyc denote cyclin B and any cyclin, respectively; CKI, Cdk inhibitory protein; CAK, Cdk-activating kinase. See text for details.

Figure 3

XErp1/Emi2 regulation in Xenopus and mouse. Depicted is the primary sequence structure of frog (upper) and mouse (lower) XErp1/Emi2, with functional elements and sites of regulatory modifications spaced according to the complete Xenopus protein. Red and green letters denote sites with negative and positive effects on XErp1’s function, respectively. Red S/T sites in Xenopus XErp1/Emi2 are targets for inhibitory phosphorylation by Cdk1, while ‘DS…’ sequences denote phosphodegrons regulating XErp1/Emi2 stability. Plx1, Xenopus Polo-like kinase 1; ZBR, zinc-binding region. See text for details.

Figure 4

XErp1/Emi2 and APC/C regulation in meiosis (A) and mitosis (B). Bars indicate XErp1/Emi2 primary structure and sequence elements as in Figure 3. Inhibitory and activating phosphorylation is depicted by red and green circles, respectively. Inactive and active APC/C or PP2A are indicated by red and green background colours, respectively. See text for details.

Figure 5

APC/C^Cdh1 regulation in mouse embryonic cell cycles and trophoblast endoreduplication cycles. (A) Mouse blastocyst with the ICM surrounded by the trophoblast. ES cells are derived from the ICM, and ES cells as well as the cells of the ICM can proliferate and differentiate to form the embryo. Cells of the trophoblast initially proliferate, then stop and undergo endoreduplication and differentiation to give rise to the placenta. (B) Pluripotent ES cell cycles are rapid and lack accentuated G1 and G2 phases (please note that ‘G1’ and ‘G2’ phases are not drawn to scale here). Emi1 inhibits APC/C activity for an extended duration, leading to increased cyclin levels that drive rapid cell cycle progression. Geminin stabilization in ES cells prevents DNA re-replication and maintains pluripotency. (C) Endoreduplicating cells of the trophoblast lineage show high APC/C^Cdh1 activity due to low levels of Emi1, resulting in the degradation of geminin, cyclin A and cyclin B. Cyclin E as the only remaining S-phase-promoting Cdk partner drives endoreduplication, facilitated by degradation of the replication re-licensing inhibitor geminin.