DEVELOPMENTAL EVENTS OF THE FIRST THREE WEEKS

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1.  Fertilization

            a)  Once released, egg and sperm die within a day or two unless fertilization occurs.  Up to 500 million sperm are deposited in the vaginal tract at intercourse, but only about 500 reach the upper third or ampulla of the uterine tube, where fertilization normally takes place.  During travel through the uterus and oviduct, sperm undergo capacitation.  Upon reaching the egg, the sperm penetrates the corona radiata and zona pellucida, undergoes the acrosome reaction, and binds to specific receptors on the egg membrane.  The membranes of the egg and sperm fuse, and rupture at the point of contact.  The head and tail of the sperm enter the egg cytoplasm, and the sperm plasma membrane is absorbed into that of the egg.  The nucleus of the secondary oocyte completes second meiotic division to form a small polar body and the female pronucleus, while the DNA of the sperm head uncoils to form the male pronucleus.  The two pronuclei migrate toward each other, replicating their DNA as they travel. The pronuclei make contact, lose their nuclear membranes, and their chromosomes intermingle to form a common metaphase plate of the first mitotic division of the zygote.

            b)  Egg activation and the beginnings of synthesis. Before fertilization, the secondary oocyte is metabolically dormant.  Fusion of egg and sperm membranes causes a series of reactions in the egg termed egg activation, that initiate the tremendous surge of metabolic and biosynthetic activities associated with the early cleavage stages of the embryo.  These events begin with alterations in ionic permeability of the egg membrane that cause membrane depolarization, a rapid influx of cytoplasmic Ca⁺⁺ ions, and initiation of transcription of RNA. All protein synthesis up to the 2-cell stage in the human is regulated by maternal mRNA. The first embryonic genes are transcribed at the 2-cell stage (Braude et al., Nature, 332:459, 1988; Kidder, Devel. Gen., 13:319-325, 1992).

            c)  Genetic results of fertilization.  Fusion of the pronuclei results in (1) restoration of the diploid number of chromosomes; (2) random segregation of maternal and paternal genetic material; and (3) determination of sex of the new individual.

2.  Cleavage.  The rate of cleavage in mammals is among the slowest in the animal kingdom.  About 30 hrs after ovulation, the zygote undergoes its first mitotic division to form a 2-cell egg.  Each blastomere then divides repeatedly, but not in synchrony, to yield a morula containing 12-16 cells by about 60 hrs. As cleavage progresses, the zygote moves down the Fallopian tube, entering the uterine cavity as a morula during the third day after fertilization.

3.  Compaction.  Up to the 8-cell stage, the blastomeres are only loosely attached to each other.  Following the third cleavage, however, they suddenly increase in mutual adhesiveness, maximizing their contact surfaces, and form a compact ball of cells. This smoothly packed arrangement is stabilized by tight junctions that form at the outside edges of the blastomeres, sealing off the inside of the sphere. At the same time, gap junctions form among the connecting blastomeres enabling small molecules and ions to pass between the cells.

4.   Blastocyst formation and implantation.  Morula cells de-adhere in specific internal regions while fluid is pumped into the intercellular space to form a segmentation cavity, which soon enlarges into a blastocoele, separating the inner cell mass or embryoblast from the outer cells or trophoblast.  The zona pellucida disappears.  The blastocyst remains free in the uterine lumen until about 6 days, at which time it consists of 200-300 cells.  Implantation begins on day 6 or 7, into the highly vascularized uterine endometrial wall.

5.  Germ-layer formation.  After implantation (during days 7-9) totipotent inner cell mass (ICM) cells migrate to the lower surface of the embryoblast and spread as the endodermal layer, while other ICM cells contribute to formation of the trophectoderm (Winkel and Pedersen, Dev. Biol. 127:143, 1988).  Within the trophectoderm the amniotic cavity forms to separate the epiblast from cytotrophoblast.  During the third week, prospective mesoderm moves from the epiblast layer through the primitive streak to spread out as a mesodermal layer between endoderm and ectoderm.