Human Early Embryo Development

An Embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination. In Humans, it is called an Embryo from the moment of Fertilization until the end of the 8th week of gestational age, whereafter it is instead called a Fetus. In organisms that reproduce sexually, once a Sperm fertilizes an Egg cell, the result is a cell called the Zygote. In animals, the development of the Zygote into an embryo proceeds through specific recognizable stages of Blastula, Gastrula, and Organogenesis. Little is known about the specific genes that regulate these early events or how interactions among cells or how cellular interactions with other factors in the three-dimensional environment of the early Embryo affect development. The processes, by which a fertilized Egg becomes an embryo, called embryogenesis, include coordinated cell division, cell specialization, cell migration, and genetically programmed cell death (Ref.1).

In Mammals, including Human, Oocyte is released from the Ovary and swept by the fimbriae into the Oviduct. The mature Oocyte, a haploid cell that contains half the normal number of chromosomes, is surrounded by a protective coat of noncellular material called the Zona Pellucida. For Fertilization to occur, a haploid Sperm cell must bind to and penetrate the Zona pellucida, fuse with the cell membrane of the Oocyte, enter the Oocyte cytoplasm, and fuse its pronucleus with the Oocyte pronucleus. Fertilization occurs in the Ampulla of the Oviduct, a region close to the Ovary. In human, the Fertilization of an Egg by a Sperm generates a Zygote. After fertilization, the Zygote makes its way to the Uterus, a journey that takes five to seven days in humans. As it travels, the Zygote divides. The first cleavage produces two identical cells and then divides again to produce four cells. Usually the cells remain together, dividing asynchronously to produce 8 cells, 16 cells, and so on. In Humans and Mice, at about the eight-cell stage, the embryo compacts, meaning that the formerly loose ball of cells comes together in a tight array that is interconnected by gap junctions. These specialized membrane structures consist of an array of six protein molecules called Connexins, which form a pore that allows the exchange of ions and small molecules between cells. By the third to fourth day the embryo develops to a compact ball of twelve or more cells called a Morula. After several more divisions, the Morula cells begin to specialize and form a hollow sphere of cells called a Blastocyst or Blastula. The outer layer of the Blastocyst is named the TE (Trophectoderm) and the cells inside ICM (Inner Cell Mass). The cells of the ICM are Pluripotent stem cells that can give rise to all cell types of the three embryonic germ layers, i.e., Ectoderm, Mesoderm, and Endoderm, and the Germ Cell Lineage, as well as to the Nontrophoblast tissues that support the developing embryo. The latter are referred to as Extraembryonic tissues and include the Yolk sac, Allantois, and Amnion (Ref.2 & 3).

Trophectoderm is the progenitor tissue of the entire outer epithelial component of the placenta, known as Trophoblast, and provides the functional bridge between the Fetus and the mother. Trophoblast, which ultimately consists of a range of terminally differentiated cell types, performs the majority of the absorptive, immunoprotective and endocrinological functions of the placenta. Although the initial Trophoblast cells of Humans divide like most other cells of the body, they give rise to a population of cells wherein nuclear division occurs in the absence of Cytokinesis. The original type of Trophoblast cells constitutes a layer called the Cytotrophoblast, whereas the multinucleated type of cell forms the Syncytiotrophoblast. By 5 to 7 days postfertilization in humans, the Blastocyst reaches the uterus. In the uterus, the Blastocyst hatches out of the Zona pellucida, the structure that originally surrounded the Oocyte and that also prevented the implantation of the Blastocyst into the wall of the oviduct. Many of the molecular and cellular events that occur during the second week of Human Embryonic development, help establish the Placenta. About post fertilization days 8 to 9 in humans, the ball-shaped embryo implants into the Uterine wall. The ICM of the human Embryo at this stage split into 2 layers. One is the Hypoblast, which lies next to the Blastocoel and gives rise to the Extraembryonic Endoderm, which forms the Yolk sac. The other cell layer that develops from the ICM is the Epiblast. The Epiblast cell layer is split by small clefts that eventually coalesce to separate the Embryonic Epiblast from the other Epiblast cells, which form the Amnionic cavity. Once the lining of the Amnion is completed, it fills with a secretion called Amnionic (Amniotic) fluid, which serves as a shock absorber for the developing Embryo while preventing its desiccation. The Embryonic Epiblast contains all the cells that will generate the actual embryo. At the start of the third week of Human development, the cells of the Embryonic Epiblast begin to differentiate. The process is known as Gastrulation and the Embryo at this stage is known as Gastrula. The process of Gastrulation begins between days 14 and 16 of Human development. At that time, a primitive streak forms in a specific region of the Epiblast along the posterior axis of the Embryo. By the end of the third week, they generate the three primary germ layers of the Embryo—Endoderm, Mesoderm, and Ectoderm. They require the activation and inactivation of specific genes at specific times, highly integrated cell-cell interactions, and interactions between cells and their non-cellular environment, the extracellular matrix. The forward-moving Epiblast cells spread laterally, a migration that induces the formation of the Mesoderm and the Notochord. The Notochord is a temporary, rod-like structure that develops along the dorsal surface of the embryo and will ultimately connect the AVE (Anterior Visceral Endoderm) and the node. Cells at the anterior end of the notochord eventually underlie the forebrain. At the anterior end of the primitive streak is the node, a two-layered structure and important signaling center in the embryo. The ventral layer of cells in the node comes from the Epiblast and generates the notochordal plate, which then forms the notochord. Endoderm, which will give rise to the Gut, also develops near the node, along the sides of the notochord. Meanwhile, the anterior region of the Mesoderm that develops from the primitive streak prepares to give rise to the heart. The Anterior Epiblast generates the Neuroectoderm and the Ectoderm that covers the surface of the Embryo. The Ectodermal tissue that lies dorsal to the Notochord will generate the Neural plate, which will round up to form the Neural tube, the precursor to the Central Nervous System (Brain and Spinal Cord) (Ref.4, 5 & 6).

Thus, the Embryonic Ectoderm, gives rise to central nervous system (Brain and Spinal Cord) and Peripheral nervous system; outer surface or Skin of the organism; Cornea and lens of the eye; epithelium that lines the mouth and nasal cavities and the anal canal; epithelium of the pineal gland, pituitary gland, and adrenal medulla; and cells of the neural crest (which gives rise to various facial structures, pigmented skin cells called Melanocytes, and dorsal root ganglia, clusters of nerve cells along the spinal cord). The embryonic Mesoderm, gives rise to skeletal, smooth, and cardiac muscle; structures of the Urogenital system (kidneys, Ureters, gonads, and reproductive ducts); bone marrow and blood; fat; bone, and cartilage; other connective tissues; and the lining of the body cavity. The embryonic Endoderm, gives rise to the epithelium of the entire digestive tract (excluding the mouth and anal canal); epithelium of the respiratory tract; structures associated with the digestive tract (liver and pancreas); Thyroid, parathyroid, and thymus glands; epithelium of the reproductive ducts and glands; epithelium of the urethra and bladder. Another important type of cells in this developmental scheme is the PG (Primordial Germ) cells, which will give rise to Eggs and Sperm in the adult organism. Prior to gastrulation, at about the time of primitive streak formation, these precursor cells split off from the proximal region of the epiblast and migrate into the Extraembryonic Mesoderm. It is not until the proximal Epiblast cells reach the Extraembryonic Mesoderm that they are committed to becoming PG cells (Ref.7 & 8).

The development of the mammalian embryo is controlled by regulatory genes, some of which regulate the transcription of other genes. These regulators activate or repress patterns of gene expression that mediate phenotypic changes during stem cell differentiation. Oct4 (Octamer Binding Transcription Factor-4) belongs to the POU (Pit-Oct-Unc) transcription factor family. The POU family of transcription factors can activate the expression of their target genes through binding an octameric sequence motif of an AGTCAAAT consensus sequence. Recent evidence indicates that Oct4 is almost exclusively expressed in ESCs (Embryonic stem Cells). During embryonic development, Oct4 is expressed initially in all Blastomeres. Subsequently, its expression becomes restricted to the ICM and down regulated in the Trophoectoderm. At maturity, Oct4 expression becomes confined exclusively to the developing Germ cells. Besides Oct4, other transcription factors like Nanog and SOX2 (SRY (Sex Determining Region-Y) Box-2) are also expressed in ICM and ESCs and are downregulated during differentiation. In Human, FGF2 (Fibroblast Growth Factor-2) maintains ESCs in the undifferentiated state. BMPs (Bone Morphogenic Proteins), on the other hand, induce differentiation into extraembryonic lineages, either in the presence or absence of serum. Several proteins take part in Embryonic differentiation. Much of the genetic and developmental information has been derived from the mouse where most information exists. In Human not much information is available. Some important proteins found in Trophoectoderm differentiation include GCM1 (Glial Cells Missing homolog-1), ID2 (Inhibitor of DNA binding-2, dominant negative helix-loop-helix protein) and Hash2. Hash2 gene is necessary for the specification of Spongiotrophoblast and Syncytiotrophoblast. Likewise, the gene, GCM1, must be active for Syncytiotrophoblast to develop from its precursors. The transcription factors believed to have a positive association with Trophectoderm specification have been inferred primarily in two ways: by their expression patterns in embryos, ES cells and TS cells and by the consequences of gene disruption on embryonic development. Many of these transcription factors also control the expression of genes characteristically expressed in trophoblast but not in the epiblast, primitive endoderm and their derivatives. ES and Trophoectoderm cells are beginning to provide insights into the changes in gene expression that accompany lineage specification and the subsequent post-specification events that lead to functional Trophoblast derivatives (Ref.9 &10).

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