Restarting life: fertilization and the transition from meiosis to mitosis
01 Sep 2013-Nature Reviews Molecular Cell Biology (Nat Rev Mol Cell Biol)-Vol. 14, Iss: 9, pp 549-562
TL;DR: Fertilization triggers a complex cellular programme that transforms two highly specialized meiotic germ cells into a totipotent mitotic embryo.
Abstract: Fertilization triggers a complex cellular programme that transforms two highly specialized meiotic germ cells, the oocyte and the sperm, into a totipotent mitotic embryo. Linkages between sister chromatids are remodelled to support the switch from reductional meiotic to equational mitotic divisions; the centrosome, which is absent from the egg, is reintroduced; cell division shifts from being extremely asymmetric to symmetric; genomic imprinting is selectively erased and re-established; and protein expression shifts from translational control to transcriptional control. Recent work has started to reveal how this remarkable transition from meiosis to mitosis is achieved.
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...The embryo then divides into a multicellular blastocyst and implants into the uterus to develop further [18]....
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...The egg only completes the second meiotic division upon fertilization by sperm [18]....
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...Chromosomes from the egg and sperm become enclosed in pronuclear envelopes, which then coalesce in preparation for the first mitotic division of the embryo (Figure 2C) [18,20]....
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150 citations
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...A successful fertilization event occurs when a sperm cell fuses with an oocyte to form a totipotent zygote and initiates embryogenesis (Clift and Schuh, 2013)....
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TL;DR: Additional, more slowly developing mechanisms involving paracrine signaling by extracellular peptide and EGF receptor ligands maintain the low level of cGMP in the oocyte.
Abstract: Meiotic progression in mammalian preovulatory follicles is controlled by the granulosa cells around the oocyte. Cyclic GMP (cGMP) generated in the granulosa cells diffuses through gap junctions into the oocyte, maintaining meiotic prophase arrest. Luteinizing hormone then acts on receptors in outer granulosa cells to rapidly decrease cGMP. This occurs by two complementary pathways: cGMP production is decreased by dephosphorylation and inactivation of the NPR2 guanylyl cyclase, and cGMP hydrolysis is increased by activation of the PDE5 phosphodiesterase. The cGMP decrease in the granulosa cells results in rapid cGMP diffusion out of the oocyte, initiating meiotic resumption. Additional, more slowly developing mechanisms involving paracrine signaling by extracellular peptides (C-type natriuretic peptide and EGF receptor ligands) maintain the low level of cGMP in the oocyte. These coordinated signaling pathways ensure a fail-safe system to prepare the oocyte for fertilization and reproductive success.
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References
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TL;DR: The study of imprinting provides new insights into epigenetic gene modification during development, and is thought to influence the transfer of nutrients to the fetus and the newborn from the mother.
Abstract: Genomic imprinting affects several dozen mammalian genes and results in the expression of those genes from only one of the two parental chromosomes. This is brought about by epigenetic instructions--imprints--that are laid down in the parental germ cells. Imprinting is a particularly important genetic mechanism in mammals, and is thought to influence the transfer of nutrients to the fetus and the newborn from the mother. Consistent with this view is the fact that imprinted genes tend to affect growth in the womb and behaviour after birth. Aberrant imprinting disturbs development and is the cause of various disease syndromes. The study of imprinting also provides new insights into epigenetic gene modification during development.
2,212 citations
TL;DR: Fully grown oocytes of the frog (Rana pipiens) undergo cytoplasmic and nuclear maturation when treated with progesterone after the follicular envelopes have been removed, and the arrest of mitosis and cleavage can be attributed to a specific “cytostatic factor” in the cy toplasm of the secondary oocyte.
Abstract: Fully grown oocytes of the frog (Rana pipiens) undergo cytoplasmic and nuclear maturation when treated with progesterone after the follicular envelopes have been removed. The mechanism of this maturation was investigated by injection of cytoplasm from progesterone-treated oocytes at various stages of maturation into fully grown but immature oocytes. The injected cytoplasm becomes effective in inducing maturation by 12 hours after progesterone administration, reaches a maximum effectiveness around 20 hours, and then declines after the donor oocytes complete maturation. However, even cytoplasm from early embryos retains some capacity to induce oocyte maturation. The frequency with which maturation is induced is proportional to the volume of the injected cytoplasm. Progesterone itself is not directly responsible for the maturation-producing effect of injected cytoplasm since injected progesterone does not promote maturation. However, externally applied progesterone does induce the completion of the first meiotic division, presumably by releasing a cytoplasmic “maturation promoting factor.” The production of this cytoplasmic factor was not affected by removal of the nucleus.
After completion of the first meiotic division, oocytes cease further development at the metaphase of the second meiotic division, where they remain until fertilized or activated to develop. Cytoplasm from such secondary oocytes when injected into one of the blastomeres at the two-cell stage of development suppresses mitosis as well as cleavage. Mitosis is usually arrested at metaphase. No such inhibition was brought about by injection of cytoplasm from cleaving blastomeres. Thus, the arrest of mitosis and cleavage can be attributed to a specific “cytostatic factor” in the cytoplasm of the secondary oocyte. Activation of donor secondary oocytes by insemination or pricking with a glass needle soon destroys the cytostatic factor. Likewise, addition of cortical cytoplasm to endoplasm from the secondary oocyte rapidly destroys the cytostatic capacity. This result implies that cortical material is involved in the process of removing the cytostatic factor at the time of normal activation or fertilization. Enucleation of oocytes demonstrated that production and removal of the cytostatic factor is independent of the nucleus.
1,508 citations
TL;DR: Changes in the pattern of polypeptides synthesized during the pre-implantation stages of human development are described, and it is demonstrated that some of the major qualitative changes which occur between the four- and eight-cell stages are dependent on transcription.
Abstract: The earliest stages of development in most animals, including the few mammalian species that have been investigated, are regulated by maternally inherited information. Dependence on expression of the embryonic genome cannot be detected until the mid two-cell stage in the mouse, the four-cell stage in the pig (J. Osborn & C. Polge, personal communication), and the eight-cell stage in the sheep. Information about the timing of activation of the embryonic genome in the human is of relevance not only to the therapeutic practice of in vitro fertilization and embryo transfer (IVF), but more importantly for the successful development of techniques for the preimplantation diagnosis of certain inherited genetic diseases. We describe here changes in the pattern of polypeptides synthesized during the pre-implantation stages of human development, and demonstrate that some of the major qualitative changes which occur between the four- and eight-cell stages are dependent on transcription. In addition, it appears that cleavage is not sensitive to transcriptional inhibition until after the four-cell stage.
1,357 citations
TL;DR: It is shown that the paternal genome in the mouse is significantly and actively demethylated within 6–8 hours of fertilization, before the onset of DNA replication, whereas the maternal genome is dem methylated after several cleavage divisions.
Abstract: In mammals, both parental genomes undergo dramatic epigenetic changes after fertilization to form the diploid somatic genome. Here we show that the paternal genome in the mouse is significantly and actively demethylated within 6–8 hours of fertilization, before the onset of DNA replication, whereas the maternal genome is demethylated after several cleavage divisions. This active demethylation of the paternal genome may be associated with epigenetic remodelling of sperm chroma-tin, in order to establish parent-specific developmental programmes during early embryogenesis.
1,332 citations
TL;DR: It is shown that juvenile and adult mouse ovaries possess mitotically active germ cells that, based on rates of oocyte degeneration (atresia) and clearance, are needed to continuously replenish the follicle pool.
Abstract: A basic doctrine of reproductive biology is that most mammalian females lose the capacity for germ-cell renewal during fetal life, such that a fixed reserve of germ cells (oocytes) enclosed within follicles is endowed at birth. Here we show that juvenile and adult mouse ovaries possess mitotically active germ cells that, based on rates of oocyte degeneration (atresia) and clearance, are needed to continuously replenish the follicle pool. Consistent with this, treatment of prepubertal female mice with the mitotic germ-cell toxicant busulphan eliminates the primordial follicle reserve by early adulthood without inducing atresia. Furthermore, we demonstrate cells expressing the meiotic entry marker synaptonemal complex protein 3 in juvenile and adult mouse ovaries. Wild-type ovaries grafted into transgenic female mice with ubiquitous expression of green fluorescent protein (GFP) become infiltrated with GFP-positive germ cells that form follicles. Collectively, these data establish the existence of proliferative germ cells that sustain oocyte and follicle production in the postnatal mammalian ovary.
1,152 citations