Human embryonic development

1. Embryonic age is from fertilisation 38 weeks. For clinical timing is 40 weeks from day of last menstrual period. Critical period is the developmental stage when embryo is susceptible to toxic agents and usually corresponds to the stage of active differentiation and morphogenesis. Varies depending on the organs. Examble of teratogens are medication like thalomide, alcohol, tobacco, caffeine, environmental chemicals, viral infection. Example thalidomide, the critical period is from3 -7 weeks (embryonic age) this causes limb development problem. Cause growth of abnormal cell masses during fetal growth resulting in defects in fetus. This was given to women as treatment for morning sickness, causes idsabilities and foetal damage. Meiosis and mitosis. Human chromosome has 46 chromosomes, 22 and xy one. Somatic cells have two sets of chromosomes diploid, a maternal and a paternal one. N + n=2n. Meiosis is the process to create haploid n cells. In mitosis, 2n to '4n' then divide into 2 as 2n. In meisosis theres meiosis 1 and 2. For 1, 2n to 4n and theres the crossover where we have homologous recombination, which allows for variation in cells, 2 to power of 23 is 8 million types. Then split back to '2n' which is in terms of dna same amount but each has only one set and different. Like have one copy of chromatin, so its like haploid ish. The split to 1n. Errors in meiosis. If nondisjunction in meiosis 1, then 2 cells have 24 chromosomes, other 2 cells have 22. If non disjunction in 2nd meiosis, within the daugther cells, one has 22, other has 24. Monosomy is when one chormosome only has a single copy, either mums or dads. In trisomy, one chromosome has 3 copies. Eg trisomy 21 is downs syndrome, where get 2 chromosomes from maternal gamete, and child has flat face, cardiac defects, growth and mental retardation, hypotonia. Eg klinefelter is when get xxy, which affects male physical and cognitive development. And turner when it is Xo instead of XX. About 30-50% of conception results in spontaneous abortion and half are due to major chromosomal abnormalities, but there are cases where the embryos can survive to birth. When meiosis occurs. In males, the primordial germ cells form from week 3-6 and then week 6-12 the pgcs migrate to the gonad. In adulthood, produce sperm by proliferation and maturation. In females, he pgc proliferate from week 3-6, migrate week 6-12, then from week 12-20 proliferation terminates, number of germ cells has reached maximum. So first meiosis occurs before birth, and then becomes dormant, in puberty, the second meiosis finishes, the egss are matured one by one. Primordial germ cells. Pgc and derivatives are only cells that can undergo meiosis, and are generated in the 3-6 week in the epiblast, near the junction with an extraembryonic tissue. The epiblast gives rise to germ cells, the endoderm, the mesoderm and the ectoderm. In the 6-12 week, they migrate to the embryonic body, and reach the genital ridge where the gonad is formed. They are called spermatogonia or oogonia in the gonad. In the genital ridge in males, the gonocyte doesnt enter meiosis, as the cell cycle arrest. In females, gonocyte enters first meiotic prophase to primar ooctye of 4n. Then cell cycle arrests.

2. spermatogenesis and oogenesis Spermatogenesis, making of spermatozoon. Pgc -> soernatigibusyn -> primary spermatocyte -> secondary spermatocyte -> spermatids -> spermatozoa. Recall, in the 3-6 weeks, the pgc are form, then 6-12 week migrate to the gonad where theyre called spermatogonium, then remain dormant. When puberty comes, the testosterone causes maturation of seminiferous tubules in the testis, this allows spermatogonia to furthur proliferate and enter meiosis. Although some spermatognia dont undergo meiosis and just remain as spermatogonia and function as stem cells. Primary to secondary8 days. Secondary to spermatid meiosis 2 is 16 days. Spermatid to spermatozoa differentiation is 24 days. Initial mitosis about 16 days so total is 64 days. In spermiogensis the differentiation of spermaids to spermatozoa, the nucleus condenses, forms acrosome, forms flagellum the mitochondria gather at midpiece and excess cytoplasm is removed. Testis made of seminiferous tubules. Sort of start at the edge of the circle and migrate to the centre. So 4 waves of synchronised differentiation stages are seen at the lumen a time in an active region. They are synchronised such that their cytoplasm is connected during meiosis. Cytoplasmic bridges form so that sperm without x chromosome(have y) can be supplied with essential protein encoded by genes on x chromosome. Spermiation, the process of being released from sertoli cell, sperm not yet motile. Sertoli cell surrounds differentiating spermatogonia and produces enzymes and growth factors, functions as a phagocyte to clean up residual cytoplasm of sperm. The leydig cell is outside the tubule and secretes testosterone. Epididymis is the resevoir for sperm, and concentrates the fluid 100 times, 1.2m long duct with peristalticcontraction and the sperm undergoes furthur maturation, mobility, and increase dependence on fructose for energy production. The seminal vesicles (60-70%) the prostate gland bulbourethral gland add nutrients and contribute to the seminal fluid. Capacitation is the final stage of maturation of sperm and takes place in female genital tract for 7 hours. Hyperactive tail movement and the acrosome reaction. Plasma membrance and acrozome membrane fuse in the tip part. Other parts acquire potential to fuse with plasma membrane of oocyte. Oogenesis. Pgc-> oogonium -> primary ooctye |stopshereuntilpuberty| -> secondary oocyte -> egg/mature ovum. Proliferation by mitosis occurs inside ovary after pgc migrate to gonad. 12 weeks of embryogenesis-> 1st meiosis, the follicle cells surround the ooctye and form primordial follice. Division of meiosis 1, becomes arrested in prophase as primary ooctye grows. Theres egg coat and cortical granules. So we have a primordial follicle. (at 5 months of embrygenesis , have 7 million primordial follicle, at birth left 0.7-2 at puberty is 700000. After puberty only a few continue with meiosis, one ovulated a month). So one follicle is one oocyte + surrounding follicular granulosa cells. Primordial follicle is primary oocyte with enlarged e=cytoplasm and flat 1 cell layer of follicular cells, in dormant status. So polar body happens when one cell takes most of cytoplasm and other receives less and becomes the polar bdy. So after puberty we get the first polar body. And the growth starts again with the primary follicle where growth starts again, the follicular cells become cuboid, proliferates into multiple layers, and forms the secondary follicle which has an antrum/cavity with fluid from granulosa cells. Then the preovulatory follice, only one chosen, has large antrum and it is now called the graafian follice. Then secondary oocyte is ovulated(polar body not yet formed). The second meiosis completed and second poilar body forms only if fertilisation occurs.

Menstrual cycle. Day 1 is first day. Day 1-5 the endometrium is sloughed after no sign of pregnancy. Aahh bleeding!. Then day 5+ follicle and thecal cells proliferate and secrete estrogen, so estrogen levels increases, causing the endometrial lining of the uterus to proliferate. Then day 13/14 the level of fsh and lh rise very sharply called the lh surge, and triggers ovulation(38 hours after lh surge) and the first meiosis completeion. Restart of meiosis, the germinal vesicle breaks down, the first meiotic prophase and 2nd meiotic prophase. The remaining corpus luteum secretes estrogen and progesteromne, make endometrium npw in secretory phase, and prepare for implantation, if nothing hapns after 4 days, it degeneraties to corpus albicans. After ovulation, fertilisation may occur at the ampulla of the uterine tube. Contraceptive pills, type 1 is estrogen and progesterone and type 2 is progesterone only. They mimic the luteal phase which i the secretory phase so the body thinks it is pregnant(normally if pregnant corpus luteum will keep secreting progesterone. Invitro fertilisation. Induce maturation of follicles by hormones including fsh and hcg, several follicles mature, and the ooctyes are collected with laparaoscopy or transvaiginal sonography. The sperm is added woohoo and successfully fertilised one undergo cleavage and then implant back into the uterus. Have also intracytoplasmic sperm injection where sperm directly injected into the oocyte cytoplasm to treat male infertility. 3. Fertilisation cleavage implantation. Fertilisation: occurs in ampulla of uterine tube if sperm is there. Path of sperm: 1% of sperm in vagina enter cervix, move to oviduct by propulsion, which takes 2-7 hours. At isthmus, become less motile. At ovulation, become more motile again, and move to the ampulla. About 200 reach here. Sperm undergoes capacitation which lasts 7 hours and is the interaction between sperm and mucosal surace. Sperm undergoes acrosome reaction where enzymes are released to penetrate zona pellucida. A) penetration of corona radiata the layer of follicle cells, capacitated sperm can pass freely through this b) penetration of zona pellucida, a layer of glycoprotein and barrier to prevent interspecies fertilisation, the binding and acrosome reaction mediated by ligans zp3 and a zona protein. Release of enzymes to penetrate. When head of sperm comes into contract with ooctye surface, the permeability of zona pellucida changes causing lysosomal enzymes to be realsed from corticol granules. Zona reaction, the zona pellucida properties changes and prevents sperm penetraction, inactivate receptor sites. C) fusion of oocyte and sperm cell membrane, the interaction between integrin on oocyte and disintegrin on sperm. The membrane between the sperm and egg fuse and the spermatozoa enters oocyte. I) corticol zona reaction ii)resume and completion of 2nd meiotic division to give 2nd polar body and definitive ooctye, and become the female pronucleus. Iii) metabolic activation of egg, the spermatozoa moves towards the female pronucleus and forms male pronucleus, the tail degenerates. Each pronucleus replicates its own DNA. Chromosomes organize on spindle for meiotic division. Now they have diploid number of choromosomes, the sex is determined and cleavage initiated. Cleavage: 2 cell to 4 cell to 8 cell .... Blastomeres: after third cleavage, forms compact ball together, compaction occurs, where tight junctions are stabilized, gap junction forms, then divides more to form morula, like 16 cells, where there is an inner and outer cell mass. The inner cell mass gives rise to the embryo while outer cell mass gives rise to trophoblast gives rise to extraembryonic tissuethe

placenta. Blastocyst formation: morula enters the uterine cavity and blastocele is the cavity in the blastocyst. Implantation: trophoblast cell begins penetrating the uterine mucosa, at time of implantation, the mucosa is in secretory phase endome, has compact spongy, basal layer. 1. Blastocyst attaches to endometrium on side of inner cell mass 2. Some trophoblast cells particularly the synctiotrophoblast invade into the endometrium and begin to form part of the placenta. 3. Cells facing the blostocoel become hypoblast to cover the blastocoel. 4. The inner cell mass becomes a flat sheet consisting of epiblast and hypoblast. 5. An additional cavity appears on the epiblast side called the amniotic cavity. So now we have an embryonic disc made up of the epiblast which gives rise to embryonic tissue(ectoderm, mesoderm, endoderm, pgc) and the hypoblast which is part of the yolk sac; and 2 cavitiies, the amniotic cavity and the yolk sac. Amniotic cavity is formed on the dorsal side of the embryo and yolk sac on the ventral side of embryo. Chorion: wall consisting of trophoblast derived cells. Continuous to placenta tissue and forms sac outside of amnion and yolk sacs. Embryonic stem cells are from inner cell mass that would have formed embryo. Twins?? 4. Gastrulation: the process of forming 3 germ layers ecto, endo and meso by future mesodermal and endodermal cells migrating out of epiblast layer. Formation of primitive streak: furrow on the epiblast layer, epiblast cells move towards centre axis and delaminate (separate into layers)(ingression). Cells that move to between the epiblast and hypoblast become the mesoderm. Cells that replace the hypoblast become the endoderm. Epiblast cells which did not delaminate become the ectoderm. Formation of notochord: primitive streak shortens as node regresses, from head to tail like a zipper action. Develops from prochordal process, floor of notochord process fuses with endoderm, some node cells left behind, notochord formed. Gastrulation is progressive in the head to tail direction, so like can be different place different stage. Main derivatives. Ectoderm: surface ectoderm mainly epidermis of skin, the nervous system, neural crest cell derivatives the melanocytes, some skull bones, adrenal medulla. Mesoderm: dermis the inner layer of skin, muscles, skeleton bones and cartilage except for head, urogenital organs except for bladder, blood vasculature and spleen. Endoderm: the digestive system and gut liver pancreas, the respiratory system the lung and trachea, the bladder, thyroid and parathyroid. Neural cells = cell committed to become either neuron or glia. Neuronal cell = cell committed to become neuron not glia, may not yet be fully differentiated. Neuron = a differentiated cell specialised for the conduction of impulses. So, neural induction is the process of inducing neural fate. Since ectoderm can be neuroectoderm and surface(non neural) ectoderm, this is just for the neuroectoderm. Neuralation: the process of making the neural tube. Cells in the neural tube are all neural, so they are becoming either neuron or glia. Neural plate has a groove, neural fold starts to close, and the

neural tube becomes closed entirely. Brain vesicles the segmented swellings are formed. The neural tube forms the central nervous system. The brain plus spinal cord. The lumen of neural tube will become ventricles and the central canal. Retina is the protruded part of the forebrain. 5. Neuralation continued. And ectoderm Neural tube closure normally takes place at 21-28 days post fertilisation in humans. In mouse and humans, the neural plate grows significantly before it closes, so it is very difficult to close. Helped by the multiple sites for closure however defects still occur. Neural tube defects( NTD) cause 1/3 of stillbirths, affect 1/1000 cases of pregnancies, 250000 cases per year.. Anecephaly: no brain, about 40% of all ntd. Exencephaly where brain is outside. Craniorachischisis: failure of closure at almost all levels. Spina bifida: failure of closure at caudal part. Open spina bifida 40% or closed. Folic acid might help to prevent this. 0.4mg/day in first 12 weeks of pregnancy. Mechanism of closure: dorsal hinge point and median hinge point. Plus cell remodelling pathways. Secondary neuralation: formation of the caudal nerual tube isnt by the neural plate folding up andmaking a tube structure, instead a mass of neural tissue the medullary cord forms a canal and becomes continuous to the rostral neural tube. Neural crest cells: they migrate out from the border between surface ectoderm and the neural plate. Becomes a) peripheral nerves - the post synaptic neurons of autonomic nervous system, sensory neurons, schwann cells, neuroglia b) melanocytes c)some cranial mesenchyme - bones (Skeletal structures derived from somites in trunk of mesoderm)(unsegmented head mesoderm and neural crest cells form skeletal structure in the head), cartilage, odontoblast. For sensory neuron, cell body gathers to form dorsal root ganglion(or posterior root ganglion) that is outside the cns(?). for motor neuron, cell body within the neural tube in the gray matter. Some neural cells are derived from the placode(thickened epithelium), part of the surface ectoderm; the neuroblasts delaminate and give like olfactory neurons, sensory neurons of 5 ,7,9,10 cranial nerves, the hair cells of the inner ear and afferent neurons. The surface ectoderm gives rise to epidermis and placode. Neural ectoderm gives rise to neural crest cells and neural tube. The neural tube is patterned along the cranial caudal axis by Hox genes. they give the pattern of cranial caudal axis segmentation. Neural tube patterned along the dorsal ventral axis by shh. Sonic hedgehog protein is part of the hedgehog family and is important for development of brain and spinal cord, important for forebrain and eyes. 6. mesoderm derivatives + embryonic folding Mesoderm is divided into the lateral plate mesoderm (somatopleure(parietal mesoderm) and splanchnopleure (visceral mesoderm)) and the intermediate mesoderm. Also have the somites and notochord. Somites are segmented units and increase one by one. It divides into the dermatome, becoming dermis in the back skin, the myotome, becoming the muscles of the body wall and limb and the

sclerotome, becoming the bone of axial skeleton vertebrae and ribs). Also have syndotome and endothelial cells. The scelerotome cells surround the neural tube and forms the vetebral column, where two halves of adjacent scelerotome form one vertebra. The first 4.5 somites contributes to the skull. Then have cervical 1-7, thoracic 1-12, lumbar 1-5, sacrum 1-5 fused. The surrounding tissues provide incutive signals so that the somite knows what to differentiate into, signals from the neural tube, notochord, surface ectoderm, intermediate lateral mesoderm. Intermediate mesoderm: gives rise to the urogenital system. Urinary system: we have mesonephros which function as excretory units from 6-10 weeks and metanephros: future kidneys from 10 weeks onwards and are eventually degraded. So 1. The uteric bud comes out of the nephric duct, has many lobes 2. Metanephric mesenchymal cells condense to form metanephros (the thing at the bottom) 3. Mesonephros degrade (the things sticking out) 4. Position of the metanephros becomes higher, ascends upwards (now not so much the thing at the bottom). Also, tubes attach to it. Genital reproductive system: male -> testis(nephric duct becomes vas deferens). Female -> gonad develops to the ovary and another duct the mullerian duct will form the oviduct. The gonad holds the primordial germ cells and becomes the testis or ovaries. The pgc migrate to the gonad.from the genital ridge?? Lateral plate mesoderm: the somatopleure/parietal mesoderm/somatic mesoderm and th splanchnopelure/visceral mesoderm/splanchnic mesoderm. Parietal lines the body caivty and vsiceral means to line the organ. Pleural cavity is space between v and p of lung. Somatopleure: gives rise to the parietal pleura, dermis of ventral trunk and limb, the bones (limbs) is the outside layer. Splanchnopleure: gives rise to the visceral pleura and smooth muscles around gut, angioblasts(endotheliad precursor cells undergo vasculogenesis to make new vessels from nothing) The intraembryonic cavity, the space between parietal and visceral becomes the peritoneal cavity. Intermediate mesoderm derived urogenital organs are back of peritoneal cavity = retroperitoneal. Formation of mesentery is from two layers of splanchnopleure, the vessels reach the gut throuhgh the space between the two layers of the mesentery. 7. endoderm Endoderm cells are located at a part of the yolk sac. So the endodermal sheet and yolk sac kind of folds, to give the foregut, midgut and hindut plus cloaca and the vitelline duct and allantois. Gut opens at the mouth. The buccopharyngeal membrane(aka oropharyngeal membrane) is formed when the anterior part of gut touches the stomadeum(pocket shaped endodermal structure) and they eventually fuse to form the mouth. Stomadeum also touches the neural tube and this forms the hypophysis which gives rist to the pituitary gland, which is below the hypothalamus and has the neurohypophysis and the adenohypophysis.

At the caudal end, the cloacal membrane fuses to the ectodermal membrane to make an opening. The cloaca is the caudal end of the gut space for excretion of poop,uring and sperm/eggs. After making an opening (yay now just dump the poop outside) the cloaca divides into the urogenital sinus which is part of(?) urinary tract and the anorectal canal which part of (?) the digestive tract. Allantois, is a sac with many vessels, and collects liquid waste during early embryogenesis. Also does gas exchange and at the later stage of embryogenesis, the wast molecules are passed on to the maternal body through placenta. Organs arising from the gut: lung bud, liver, gallbladder, pancreas, urinary bladder. Development of intestin: gut is continuous to the yolk sac via the vitelline duct. The vitelline duct eventually closes and disappears. The intestine develops very rapidly and runs out of space in the abdominal cavity and so uses the space in umbilical cord for 6-10 weeks (physiological herniation). The loop of the intestine starts to rotate in the umbilical cord and the loop returns to the abdominal cavity when the body becomes large. The gut rotates while maintaining the mesentery. Defects in umbilicus: merkels diverticulum: when the vitelline duct does not close or separate from the body wall properly. Fistula, cyst or ligament there. Defect of ventral body wall : omphalocele, where the body folding and fusion fails to occur poperly during the 4th to 8th weeks, causes body wall weakness that causes the bowel to herniate later. Also, umbilical hernia, where a small part of the intestine remains in the umbilical cord(still covered by skin). The foregut has the celiac artery, the midgut is the superior mesenteric artery, the hindgut is the inferior mesenteric artery. The trachea and lung buds derived from a part of the gut. The epithelial lining of the respiraotry tract is of endodermal origin. If trachea fails to separate from esophagus, then got problemesophageal atresia and tracheo esophageal fistula. The liver gallbladder and pancreas are a part of the digestive system. Ducts from the testis and kidney attaches to the urinary bladder. The vas from testis, ureter from kidney, and trigone are from mesodermal origin, trigone is a triangylar area between two ureteral orifices and a urethral orifice. The lining epithelium of the urinary bladder originates from the endoderm except for the trigone area. The urinary bladder was a part of the cloaca. 8. pharyngeal arches and cranial development. Pharygeal arches are seen transiently during early embryogenesis about 5-6 weeks. 1 is the most prominent. And is the mandibular prominence. 5 disappears at an early stage, and has a different structure. Pharynx is formed when the right and left pharyngeal arches fuse at the front. Failure of the fusion of maxillary prominence results in cleft lip and cleft palate(7-10 week). The mouth is formed between the maxillary prominence and pharyngeal arch 1 (mandibular prominence) Each pharyngeal arch full of neural crest cells and cranial mesoderm. Neural crest cells migrate into each pharyngeal arch. Each arch contains muscles, cartilage, vessels, nerves. Mandibular c5 nerve in arch 1, facial nerve c7 in arch 2, glossopharyngeal nerve c9 in arch 3, vagus nerve c10 in arch 4 and 6.

Muscles for mastication from arch 1 innervated by the mandibular nerve. Muscles for facial expression from arch 2 innervated by the facial nerve. Mandibular nerve is a branch of the trigeminal nerve. The vessels transform dramatically to form great vessels, the branches disappear assymetrically, this explains how the right and left recurrent vagal nerves loop differently. Cartilage and bone also forms. Pharyngeal cleft: the groove of the ectoderm on the outside. Pharyngeal pouch: groove on the endoderm on the inside. Cleft 1: gives the external acoustic meatus, the era hole. Pouch 1 gives the typanic cavity and the auditory tube(the eustachian tube the pharyngotypanic tube). In the middle between the two pouches on left and right is the foramen cecum. Pouch 2 gives the palatine tonsil. Pouch 3 gives the inferior parathyroid gland and the thymus. Pouch 4 gives the superior parathyroid gland. And also the ultimobranchial body. Inbetween the pouch 4 is the laryngeal orifice. The 2-4 pouches migrate downwards. Pharyngeal endoderm on the midline, at the pouch 1 level, it gives the future 1/3 anterior of tongue. At the pouch 2/3 level, gives 2/3 posterior of tongue. At the pouch 4 level, gives the future epiglottis. The laryngeal orifice opens to the trachea. The foramen cecum, the endodermal cells go deep and form the thyroid gland. The thyroid gland descends from the foramen cecum spot on the tongue and secretes thyroid hormones. The pass(thryoglossal duct) may remain and form a cyst called thyroglossal cyst. The parathyroid glands descned from the pouch 3 and 4 and embedd= in the posterior surface of the thyroid gland, they secrete parathyroid hormone. The skull develops through endochondral ossification(mesenchymal cells become cartilage and then bone) and intramembranous ossification (mesenchymal cells to bone). Sutures are where two membranous bone meet. Premature closure of sutures leads to craniosynostosis, where the high pressure restricts brain development. Occurs in 1/2500 births and leads to a deformed skull and brain.