Early Embryonic Development

Early Implantation (6-7 days)

- At day 6, the blastocyst attaches to the endometrium usually adjacent to the ICM at the embryonic pole. - The trophoblast layer proliferates rapidly and differentiates into two layers: (1) inner cytotrophoblast (cellular trophoblast) (2) an outer syncitiotrophoblast (syncitial trophoblast) - The syncitiotrophoblast invades rapidly into the endometrium by developing finger-like processes to nourish the embryo

Compaction of Blastomeres (day 3-4)

- At the 8-cell stage (day 3), blastomeres change shape producing a compact ball of cells called a morula ("grape-like") - Mediated by cadherins (homophilic interaction) - Necessary to establish first of embryo polarity: inner cell mass (ICM, which develops into the embryo proper) and trophoblast (which eventually becomes the placenta) - Early cleavages that form the morula occur in the fallopian tube

Formation of the Blastocyst (4-5 days)

- By 4-5 days, the morula arrives in the uterus. - The morula cleaves further and develops into an early blastocyst. - It begins to form a blastocoel cavity filled with fluid - The blastocyst sheds the zona pellucida as it expands in size because of the hydrodynamic pressure from the fluid filling the blastocoel (blastocyst hatching/ZP shedding). - No overall size increase is possible unless the embryo sheds the zona pellucida/blastocyst hatches - Contains the ICM, the trophoblast, and the blastocoel

Cell Polarity of Morula

- The ICM will form the embryo, amnion, yolk sac, and small portions of the placenta - The ICM is the source of embryonic stem cells (ES cells) - The trophoblast forms most of the placenta

Spontaneous Abortion (Miscarriages)

- Late and very profuse menses may be instead the expulsion of a spontaneously aborted pregnancy. - Several studies have shown that the overall early spontaneous abortion rate is ~50%. - Most spontaneously aborted embryos that have been studied were grossly abnormal - Major causes of early (first trimester) spontaneous abortions: 1. Chromosomal abnormalities 55-65% (mostly 16 or 22) 2. Cleavage problems 15-25% 3. Progesterone insufficiency 10-20% - The early losses keep the rate of congenital malformations at birth to 2-3% (0.1% in teenage mothers; >10% in mothers in their late 40's).

Early Cleavage Problems

- Non-disjunction and chromosome translocation or deletion can occur during mitotic cleavages, producing an embryo with two or more genetically-different cell lines. - When these chromosomal abnormalities occur during the first several cleavages, the defect is considered "complete" and the embryo is unlikely to survive to birth unless it's a very, very minor defect. - The later in development the abnormality occurs, the more likely it is that the embryo/fetus will be born, although usually with mild-severe congenital defects. These individuals are called "mosaics". - Individuals who are mosaics generally have less severe phenotypes than those with complete non-disjunction, deletion, or translocation events. - The earlier the non-disjunction or translocation occurs, the more severe it will be because more derived daughter cells.

Completion of Implantation (12 - 14 days)

- Syncitiotrophoblast produces hCG - hCG in the maternal circulation ensures survival of the corpus luteum and its continued production of progesterone - hCG is measured in pregnancy tests: hCG levels are high enough to be detectable 3-4 days after fertilization - Endometrial stromal cells around the implantation site are called decidual cells; they produce prostaglandin E2, which blocks activation of T-cells and natural killer (NK) cells, thus providing immunologic immunity for the embryo

Overview of First 17 Days of Development

- The zygote cleaves into blastomeres for 2-3 days without any increase in overall size due to the continued presence of the zona pellucida. - By day 3, it forms a morula that consists of outer cells that form the trophoblast (cells that will go on to form the placenta and extra-embryonic tissues) and inner cell mass (cells that will form the embryo). - Further cleavages form the early blastocyst at day 4-5, and causes shedding of the zona pellucida (hatching) within a day or two. This permits the embryo to begin the implantation process. - A late blastocyst is formed during days 12-14, about a week after the beginning of implantation at day 6-7. - Implantation is completed by the end of the second week after fertilization, when the bilaminar embryonic disc is formed. - The three germ layers of the embryo are formed during the third week by gastrulation. **The sequence of all of the above is important!

Early Cleavages (days 2.5-3)

- The zygote, still inside the zona pellucida, undergoes synchronous mitotic divisions during its passage down the fallopian tube (first 3 days). - Zona pellucida prevents the zygote from adhering to the walls of the fallopian tube and causing an ectopic pregnancy. - Within 24-30 hours, the first cleavage occurs to form the first two blastomeres. - By 48-60 hours, 8 blastomeres have formed without any increase in the size of the embryo (due to the presence of the zona pellucida). This is termed compaction. ** These cells are referred to as blastomeres because they are all identical up to this point. 2 of them can be plucked without harm to the embryo and used for pre-implantation genetic diagnosis (PGD). Remember that the current best method for PGD uses several trophoblast cells from a early (Day 5) blastocyst

Gastrulation (14 days)

1) All 3 cell layers come from the epiblast 2) Hypoblast layer delaminates to allow endoderm formation 3) Trophoblast gives rise to placenta and most extra- embryonic tissues

Final Development

All the embryonic cells and critical structures and systems are pretty much in place by the end of Week 8—after that it's pretty much organizing, growing, and shaping the tissues and organs. A Week 9 embryo looks quite a bit like a tiny version of a full-term fetus.

Mid-Implantation (8 - 12 days)

Contains a bilaminar structure consisting of the epiblast (eventually forms all 3 germ layers to give rise to first 3D structure that gives rise to all of the structures in the embryo) and the hypoblast (forms the amniotic fluid and the yolk sac)

Timeline of Early Development in Humans

Eureka Moment (membrane fusion/ICSI) = Day -1 Fertilization complete (pronuclei fuse) = Day 0 2-cell embryo (first embryonic cleavage) = Day 1 4-cell embryo = Day 2 8 cell embryo (embryo biopsy stage) = Day 2.5 - 3 Morula (compaction) = 3-4 Blastocyst (implantation period) = Day 4 - 14 Gastrula = Day 15 - 17

Gametogenesis Overview

Males - Make sperm from puberty until death; from the 20-week embryo until puberty, they have immature spermatogonia (diploid sperm progenitor cells) in the testes, awaiting their testosterone-induced awakening at puberty Females - 8-20 weeks of gestation -- progenitor germ cells (oogonia) become primary (immature) oocytes arrested in prophase of Meiosis I birth -- same as 20 weeks of gestation: primary oocytes arrested in prophase of Meiosis I puberty -- ovaries still contain essentially 100% primary oocytes (still in Meiosis I) that are now capable of developing into secondary oocytes arrested in metaphase of Meiosis II and ready for ovulation during the menstrual cycle; about 10 secondary oocytes will be in the final race to be ovulated during each menstrual cycle. Until the age of about 45-50, ie, even at the start of menopause, the vast majority of oocytes are still primary oocytes arrested in prophase of Meiosis I ovulation -- secondary (mature) oocyte arrested in metaphase of Meiosis II fertilization -- membrane fusion stimulates oocyte to complete Meiosis II. The oocyte immediately goes through the rest of Meiosis II, and in an hour or so the zygote will have 2 pronuclei—one from the sperm and one from the egg. The pronuclei fuse and go through a round of DNA replication to double the number of chromosomes, and then undergo the first zygotic cleavage, which is a mitotic division that produces 2 equal daughter cells (blastomeres) each with a full complement of chromosomes. menopause -- end of fertile period; no more healthy oocytes available for ovulation; typical age = 48-55