Human embryonic development

Fertilization Fertilization takes place when the spermatozoon has successfully entered the ovum and the two sets of genetic material carried by the gametes fuse together, resulting in the zygote (a single diploid cell). This usually takes place in the ampulla of one of the fallopian tubes. The zygote contains the combined genetic material carried by both the male and female gametes which consists of the 23 chromosomes from the nucleus of the ovum and the 23 chromosomes from the nucleus of the sperm. The 46 chromosomes undergo changes prior to the mitotic division which leads to the formation of the embryo having two cells. Successful fertilization is enabled by three processes, which also act as controls to ensure species-specificity. The first is that of chemotaxis which directs the movement of the sperm towards the ovum. Secondly, an adhesive compatibility between the sperm and the egg occurs. With the sperm adhered to the ovum, the third process of acrosomal reaction takes place; the front part of the spermatozoan head is capped by an acrosome which contains digestive enzymes to break down the zona pellucida and allow its entry. The entry of the sperm causes calcium to be released which blocks entry to other sperm cells. The granules also fuse with the plasma membrane and modify the zona pellucida in such a way as to prevent further sperm entry. Cleavage The beginning of the cleavage process is marked when the zygote divides through mitosis into two cells. This mitosis continues and the first two cells divide into four cells, then into eight cells and so on. Each division takes from 12 to 24 hours. The zygote is large compared to any other cell and undergoes cleavage without any overall increase in size. This means that with each successive subdivision, the ratio of nuclear to cytoplasmic material increases. Initially, the dividing cells, called blastomeres ( Greek for sprout), are undifferentiated and aggregated into a sphere enclosed within the zona pellucida of the ovum. When eight blastomeres have formed, they start to compact. They begin to develop gap junctions, enabling them to develop in an integrated way and co-ordinate their response to physiological signals and environmental cues. When the cells number around sixteen, the solid sphere of cells within the zona pellucida is referred to as a morula. Blastulation and trophoblast Cleavage itself is the first stage in blastulation, the process of forming the blastocyst. Cells differentiate into an outer layer of cells called the trophoblast, and an inner cell mass. With further compaction the individual outer blastomeres, the trophoblasts, become indistinguishable. They are still enclosed within the zona pellucida. This compaction serves to make the structure watertight, containing the fluid that the cells will later secrete. The inner mass of cells differentiate to become embryoblasts and polarise at one end. They close together and form gap junctions, which facilitate cellular communication. This polarisation leaves a cavity, the blastocoel, creating a structure that is now termed the blastocyst. (In animals other than mammals, this is called the blastula). The trophoblasts secrete fluid into the blastocoel. The resulting increase in size of the blastocyst causes it to hatch through the zona pellucida, which then disintegrates. the amnion, yolk sac and allantois, while the fetal part of the placenta will form from the outer trophoblast layer. The embryo plus its membranes is called the conceptus, and by this stage the conceptus has reached the uterus. The zona pellucida ultimately disappears completely, and the now exposed cells of the trophoblast allow the blastocyst to attach itself to the endometrium, where it will implant. The formation of the hypoblast and epiblast, which are the two main layers of the bilaminar germ disc, occurs at the beginning of the second week. Both the embryoblast and the trophoblast will turn into two sub-layers. The inner cells will turn into the hypoblast layer, which will surround the other layer, called the epiblast, and these layers will form the embryonic disc that will develop into the embryo. Subsequently, new cells derived from yolk sac will be established between trophoblast and exocoelomic membrane and will give rise to extra-embryonic mesoderm, which will form the chorionic cavity. The villi begin to branch and contain blood vessels of the embryo. Other villi, called terminal or free villi, exchange nutrients. The embryo is joined to the trophoblastic shell by a narrow connecting stalk that develops into the umbilical cord to attach the placenta to the embryo. Arteries in the decidua are remodelled to increase the maternal blood flow into the intervillous spaces of the placenta, allowing gas exchange and the transfer of nutrients to the embryo. Waste products from the embryo will diffuse across the placenta. As the syncytiotrophoblast starts to penetrate the uterine wall, the inner cell mass (embryoblast) also develops. The inner cell mass is the source of embryonic stem cells, which are pluripotent and can develop into any one of the three germ layer cells, and which have the potency to give rise to all the tissues and organs. Embryonic disc The embryoblast forms an embryonic disc of two layers, the upper layer is called the epiblast and the lower layer, the hypoblast. The disc is stretched between what will become the amniotic cavity and the yolk sac. The epiblast is adjacent to the trophoblast and made of columnar cells; the hypoblast is closest to the blastocyst cavity and made of cuboidal cells. The epiblast migrates away from the trophoblast downwards, forming the amniotic cavity, the lining of which is formed from amnioblasts developed from the epiblast. The hypoblast is pushed down and forms the yolk sac (exocoelomic cavity) lining. Some hypoblast cells migrate along the inner cytotrophoblast lining of the blastocoel, secreting an extracellular matrix along the way. These hypoblast cells and extracellular matrix are called Heuser's membrane (or the exocoelomic membrane), and they cover the blastocoel to form the yolk sac (or exocoelomic cavity). Cells of the hypoblast migrate along the outer edges of this reticulum and form the extraembryonic mesoderm; this disrupts the extraembryonic reticulum. Soon pockets form in the reticulum, which ultimately coalesce to form the chorionic cavity (extraembryonic coelom). ==Gastrulation==

of the three germ layers , yolk sac and embryo (measuring 3 mm at five weeks) The primitive streak, a linear collection of cells formed by the migrating epiblast, appears, and this marks the beginning of gastrulation, which takes place around the seventeenth day (week 3) after fertilization. The process of gastrulation reorganises the two-layer embryo into a three-layer embryo, and also gives the embryo its specific head-to-tail, and front-to-back orientation, by way of the primitive streak which establishes bilateral symmetry. A primitive node (or primitive knot) forms in front of the primitive streak which is the organiser of neurulation. A primitive pit forms as a depression in the centre of the primitive node which connects to the notochord which lies directly underneath. The node has arisen from epiblasts of the amniotic cavity floor, and it is this node that induces the formation of the neural plate which serves as the basis for the nervous system. The neural plate will form opposite the primitive streak from ectodermal tissue which thickens and flattens into the neural plate. The epiblast in that region moves down into the streak at the location of the primitive pit where the process called ingression, which leads to the formation of the mesoderm takes place. This ingression sees the cells from the epiblast move into the primitive streak in an epithelial-mesenchymal transition; epithelial cells become mesenchymal stem cells, multipotent stromal cells that can differentiate into various cell types. The hypoblast is pushed out of the way. The epiblast keeps moving and forms a second layer, the mesoderm. The epiblast has now differentiated into the three germ layers of the embryo, so that the bilaminar disc is now a trilaminar disc, the gastrula. The three germ layers are the ectoderm, mesoderm and endoderm, and are formed as three overlapping flat discs. It is from these three layers that all the structures and organs of the body will be derived through the processes of somitogenesis, histogenesis and organogenesis. The embryonic endoderm is formed by invagination of epiblastic cells that migrate to the hypoblast, while the mesoderm is formed by the cells that develop between the epiblast and endoderm. In general, all germ layers will derive from the epiblast. The upper layer of ectoderm will give rise to the outermost layer of skin, central and peripheral nervous systems, eyes, inner ear, and many connective tissues. The middle layer of mesoderm will give rise to the heart and the beginning of the circulatory system as well as the bones, muscles and kidneys. The inner layer of endoderm will serve as the starting point for the development of the lungs, intestines, thyroid, pancreas and bladder. Following ingression, a blastopore develops where the cells have ingressed, in one side of the embryo and it deepens to become the archenteron, the first formative stage of the gut. As in all deuterostomes, the blastopore becomes the anus whilst the gut tunnels through the embryo to the other side where the opening becomes the mouth. With a functioning digestive tube, gastrulation is now completed and the next stage of neurulation can begin. ==Neurulation==

Following gastrulation, the ectoderm gives rise to epithelial and neural tissue, and the gastrula is now referred to as the neurula. The neural plate that has formed as a thickened plate from the ectoderm, continues to broaden and its ends start to fold upwards as neural folds. Neurulation refers to this folding process whereby the neural plate is transformed into the neural tube, and this takes place during the fourth week. They fold, along a shallow neural groove which has formed as a dividing median line in the neural plate. This deepens as the folds continue to gain height, when they will meet and close together at the neural crest. The cells that migrate through the most cranial part of the primitive line form the paraxial mesoderm, which will give rise to the somitomeres that in the process of somitogenesis will differentiate into somites that will form the sclerotomes, the syndetomes, the myotomes and the dermatomes to form cartilage and bone, tendons, dermis (skin), and muscle. The intermediate mesoderm gives rise to the urogenital tract and consists of cells that migrate from the middle region of the primitive line. Other cells migrate through the caudal part of the primitive line and form the lateral mesoderm, and those cells migrating by the most caudal part contribute to the extraembryonic mesoderm. ==Development of organs and organ systems==

Organogenesis is the development of the organs that begins during the third to eighth week, and continues until birth. Sometimes full development, as in the lungs, continues after birth. Different organs take part in the development of the many organ systems of the body. Blood Haematopoietic stem cells that give rise to all the blood cells develop from the mesoderm. The development of blood formation takes place in clusters of blood cells, known as blood islands, in the yolk sac. Blood islands develop outside the embryo, on the umbilical vesicle, allantois, connecting stalk, and chorion, from mesodermal hemangioblasts. In the centre of a blood island, hemangioblasts form the haematopoietic stem cells that are the precursor to all types of blood cell. In the periphery of a blood island the hemangioblasts differentiate into angioblasts, the precursors to the blood vessels. Heart and circulatory system The heart is the first functional organ to develop and starts to beat and pump blood at around 22 days. Cardiac myoblasts and blood islands in the splanchnopleuric mesenchyme on each side of the neural plate give rise to the cardiogenic region. Also at the same time that the endocardial tubes are forming, vasculogenesis (the development of the circulatory system) has begun. This starts on day 18 with cells in the splanchnopleuric mesoderm differentiating into angioblasts that develop into flattened endothelial cells. These join to form small vesicles called angiocysts which join up to form long vessels called angioblastic cords. These cords develop into a pervasive network of plexuses in the formation of the vascular network. This network grows by the additional budding and sprouting of new vessels in the process of angiogenesis. The midgut forms the primary intestinal loop, from which originates the distal duodenum to the entrance of the bile duct. The loop continues to the junction of the proximal two-thirds of the transverse colon with the distal third. At its apex, the primary loop remains temporarily in open connection with the yolk sac through the vitelline duct. During the sixth week, the loop grows so rapidly that it protrudes into the umbilical cord (physiological herniation). In the 10th week, it returns into the abdominal cavity. While these processes are occurring, the midgut loop rotates 270° counterclockwise. Common abnormalities at this stage of development include remnants of the vitelline duct, failure of the midgut to return to the abdominal cavity, malrotation, stenosis, and duplication of parts. Respiratory system The respiratory system develops from the lung bud, which appears in the ventral wall of the foregut about four weeks into development. The lung bud forms the trachea and two lateral growths known as the bronchial buds, which enlarge at the beginning of the fifth week to form the left and right main bronchi. These bronchi in turn form secondary (lobar) bronchi; three on the right and two on the left (reflecting the number of lung lobes). Tertiary bronchi form from secondary bronchi. While the internal lining of the larynx originates from the lung bud, its cartilages and muscles originate from the fourth and sixth pharyngeal arches. Urinary system Kidneys Three different kidney systems form in the developing embryo: the pronephros, the mesonephros and the metanephros. Only the metanephros develops into the permanent kidney. All three are derived from the intermediate mesoderm. Pronephros The pronephros derives from the intermediate mesoderm in the cervical region. It is not functional and degenerates before the end of the fourth week. Mesonephros The mesonephros derives from intermediate mesoderm in the upper thoracic to upper lumbar segments. Excretory tubules are formed and enter the mesonephric duct, which ends in the cloaca. The mesonephric duct atrophies in females, but participate in development of the reproductive system in males. Metanephros The metanephros appears in the fifth week of development. An outgrowth of the mesonephric duct, the ureteric bud, penetrates metanephric tissue to form the primitive renal pelvis, renal calyces and renal pyramids. The ureter is also formed. Bladder and urethra Between the fourth and seventh weeks of development, the urorectal septum divides the cloaca into the urogenital sinus and the anal canal. The upper part of the urogenital sinus forms the bladder, while the lower part forms the urethra. Above the mesencephalon is the prosencephalon (future forebrain) and beneath it is the rhombencephalon (future hindbrain). Cranial neural crest cells migrate to the pharyngeal arches as neural stem cells, where they develop in the process of neurogenesis into neurons. The optical vesicle (which eventually becomes the optic nerve, retina and iris) forms at the basal plate of the prosencephalon. The alar plate of the prosencephalon expands to form the cerebral hemispheres (the telencephalon) whilst its basal plate becomes the diencephalon. Finally, the optic vesicle grows to form an optic outgrowth. ==Development of physical features==

Face and neck From the third to the eighth week the face and neck develop. Ears The inner ear, middle ear and outer ear have distinct embryological origins. Inner ear At about 22 days into development, the ectoderm on each side of the rhombencephalon thickens to form otic placodes. These placodes invaginate to form otic pits, and then otic vesicles. The otic vesicles then form ventral and dorsal components. The ventral component forms the saccule and the cochlear duct. In the sixth week of development the cochlear duct emerges and penetrates the surrounding mesenchyme, travelling in a spiral shape until it forms 2.5 turns by the end of the eighth week. The saccule is the remaining part of the ventral component. It remains connected to the cochlear duct via the narrow ductus reuniens. The dorsal component forms the utricle and semicircular canals. Middle ear The first pharyngeal pouch lengthens and expands to form the tubotympanic recess. This recess differentiates to form most of the tympanic cavity of the middle ear, and all of the Eustachian or auditory tube. The narrow auditory tube connects the tympanic cavity to the pharynx. The bones of the middle ear, the ossicles, derive from the cartilages of the pharyngeal arches. The malleus and incus derive from the cartilage of the first pharyngeal arch, whereas the stapes derives from the cartilage of the second pharyngeal arch. Outer ear The external auditory meatus develops from the dorsal portion of the first pharyngeal cleft. Six auricular hillocks, which are mesenchymal proliferations at the dorsal aspects of the first and second pharyngeal arches, form the auricle of the ear. Eyes The eyes begin to develop from the third week to the tenth week. Limbs At the end of the fourth week limb development begins. Limb buds appear on the ventrolateral aspect of the body. They consist of an outer layer of ectoderm and an inner part consisting of mesenchyme which is derived from the parietal layer of lateral plate mesoderm. Ectodermal cells at the distal end of the buds form the apical ectodermal ridge, which creates an area of rapidly proliferating mesenchymal cells known as the progress zone. Cartilage (some of which ultimately becomes bone) and muscle develop from the mesenchyme. ==Clinical significance==

Toxic exposures in the embryonic period can be the cause of major congenital malformations, since the precursors of the major organ systems are now developing. Each cell of the preimplantation embryo has the potential to form all of the different cell types in the developing embryo. This cell potency means that some cells can be removed from the preimplantation embryo and the remaining cells will compensate for their absence. This has allowed the development of a technique known as preimplantation genetic diagnosis, whereby a small number of cells from the preimplantation embryo created by IVF, can be removed by biopsy and subjected to genetic diagnosis. This allows embryos that are not affected by defined genetic diseases to be selected and then transferred to the pregnant woman's uterus. Sacrococcygeal teratomas, tumours formed from different types of tissue, that can form, are thought to be related to primitive streak remnants, which ordinarily disappear. First arch syndromes are congenital disorders of facial deformities, caused by the failure of neural crest cells to migrate to the first pharyngeal arch. Spina bifida a congenital disorder is the result of the incomplete closure of the neural tube. Vertically transmitted infections can be passed from the pregnant woman to the unborn child at any stage of its development. Hypoxia a condition of inadequate oxygen supply can be a serious consequence of a preterm or premature birth. == See also ==

File:Didactic model of a human embryonic development 01.jpg|Representing different stages of embryogenesis File:Didactic model of a human embryonic development 05.jpg|Early stage of the gastrulation process File:Didactic model of a human embryonic development 03.jpg|Phase of the gastrulation process File:Didactic model of a human embryonic development 04.jpg|Top of the form of the embryo File:Didactic model of a human embryonic development 02.jpg|Establishment of embryo medium File:Sobo 1909 621.png|Spinal cord at five weeks File:Gray947.png|Head and neck at 32 days == References ==