Mos in the oocyte: how to use MAPK independently of growth factors and transcription to control meiotic divisions

Abstract

In many cell types, the mitogen-activated protein kinase (MAPK) also named extracellular signal-regulated kinase (ERK) is activated in response to a variety of extracellular growth factor-receptor interactions and leads to the transcriptional activation of immediate early genes, hereby influencing a number of tissue-specific biological activities, as cell proliferation, survival and differentiation. In one specific cell type however, the female germ cell, MAPK does not follow this canonical scheme. In oocytes, MAPK is activated independently of growth factors and tyrosine kinase receptors, acts independently of transcriptional regulation, plays a crucial role in controlling meiotic divisions, and is under the control of a peculiar upstream regulator, the kinase Mos. Mos was originally identified as the transforming gene of Moloney murine sarcoma virus and its cellular homologue was the first proto-oncogene to be molecularly cloned. What could be the specific roles of Mos that render it necessary for meiosis? Which unique functions could explain the evolutionary cost to have selected one gene to only serve for few hours in one very specific cell type? This review discusses the original features of MAPK activation by Mos and the roles of this module in oocytes.

Figure 1

Progression through meiosis and timing of fertilization: what does Mos do? Oocytes are arrested at prophase of the first meiotic division (prophase I). Under response to a physiological stimulus, MPF is activated and promotes breakdown of the nuclear envelope (GVBD for germinal vesicle breakdown) and formation of the metaphase I spindle. In insects, molluscs, and ascidians, oocytes arrest at metaphase I until fertilization. In the other cases, oocytes extrude the first polar body and enter the second meiotic division. In vertebrates, they arrest at metaphase II until fertilization. In echinoderms and cnidarians, they complete the second meiotic division by emitting the second polar boy, reform a nucleus (female pronucleus), and stop at the G1 phase of the first cell cycle until fertilization. In different species including the nematode Caenorhabditis elegans, fertilization occurs at prophase I and corresponds to the stimulus promoting meiotic maturation. Mos has been implicated: (i) in the initial step of MPF activation during reinitiation of meiotic division, (ii) during the metaphase I to metaphase II transition for the suppression of S-phase, for the microtubular spindle organization and for the reactivation of MPF to enter meiosis II, and (iii) in the arrest of oocyte maturation before fertilization.

Figure 2

Patterns of Mos expression and MPF activity during oocyte meiotic maturation and at fertilization in Xenopus, mouse, and starfish. Prophase I-arrested oocytes require a physiological stimulus to undergo meiotic maturation: progesterone in frogs, release from the follicle in mammals, and 1-methyl-adenine in starfish. Once activated, MPF promotes entry into the first meiotic division: breakdown of the nuclear envelope (GVBD for germinal vesicle breakdown) and formation of the metaphase I spindle (MI). MPF activity falls due to partial cyclin degradation at meiosis I/meiosis II transition or interkinesis (IK), during which chromosomes remain condensed without nuclear membranes and in the absence of DNA replication. MPF rises again leading to entry into meiosis II. In vertebrates, oocytes arrest at metaphase II (MII), while in echinoderms, oocytes complete the second meiotic division and arrest at the G1 phase. Mos translational timing is different among species, occurring before MPF activation in Xenopus (however, Mos protein is unstable until GVBD and MAPK activity is detected only at time of MPF activation, not illustrated) and during metaphase I in other species.

Figure 3

Meiotic arrest of the unfertilized oocyte: the downstream effectors of Mos/MAPK. In all species, oocytes halt meiosis to prevent embryonic development in the absence of fertilization. Depending on species, meiosis arrests at prophase I, metaphase I, metaphase II, or G1 following meiosis. Except in C. elegans, Mos was found to be the ubiquitous cytostatic factor responsible for the unfertilized oocyte arrest. Its downstream targets accounting for the meiotic arrest of the unfertilized oocytes are indicated.