Human embryonic development

Human embryonic developmentorhuman embryogenesisis the development and formation of the humanembryo.It is characterised by the processes ofcell divisionandcellular differentiationof the embryo that occurs during the early stages of development. In biological terms, thedevelopment of the human bodyentails growth from a one-celledzygoteto an adulthuman being.Fertilizationoccurs when thesperm cellsuccessfully enters andfuseswith anegg cell(ovum). The genetic material of the sperm and egg then combine to form the single cell zygote and the germinal stage of development commences. Human embryonic development covers the first eight weeks of development, which have 23 stages, calledCarnegie stages.At the beginning of the ninth week, the embryo is termed afetus(spelled "foetus" inBritish English). In comparison to the embryo, the fetus has more recognizable external features and a more complete set of developing organs.

Human embryologyis the study of this development during the first eight weeks after fertilization. The normal period ofgestation(pregnancy) is about nine months or 40 weeks.

The germinal stage refers to the time from fertilization through the development of the early embryo untilimplantationis completed in theuterus.The germinal stage takes around 10 days.^[1]During this stage, the zygote divides in a process calledcleavage.Ablastocystis then formed and implants in theuterus.Embryogenesis continues with the next stage ofgastrulation,when the threegerm layersof the embryo form in a process calledhistogenesis,and the processes ofneurulationandorganogenesisfollow.

The entire process of embryogenesis involves coordinated spatial and temporal changes ingene expression,cell growth,andcellular differentiation.A nearly identical process occurs in other species, especially amongchordates.

Germinal stage

Fertilization

Fertilization takes place when thespermatozoonhas successfully entered the ovum and the two sets of genetic material carried by thegametesfuse together, resulting in the zygote (a singlediploidcell). This usually takes place in the ampulla of one of thefallopian 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 themitotic divisionwhich 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 ofchemotaxiswhich directs the movement of the sperm towards the ovum.^[2]Secondly, an adhesive compatibility between the sperm and the egg occurs. With the sperm adhered to the ovum, the third process ofacrosomal reactiontakes place; the front part of the spermatozoan head is capped by anacrosomewhich contains digestiveenzymesto break down thezona pellucidaand allow its entry.^[3]The entry of the sperm causes calcium to be released which blocks entry to other sperm cells.^[3]A parallel reaction takes place in the ovum called thezona reaction.This sees the release ofcortical granulesthat release enzymes which digest sperm receptor proteins, thus preventingpolyspermy.^[4]The granules also fuse with the plasma membrane and modify the zona pellucida in such a way as to prevent further sperm entry.

Cleavage

Eight-cell embryo, at three days

The beginning of thecleavageprocess is marked when the zygote divides throughmitosisinto 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.^[5]

Initially, the dividing cells, calledblastomeres(blastosGreek for sprout), are undifferentiated and aggregated into a sphere enclosed within thezona pellucidaof the ovum. When eightblastomereshave formed, they start tocompact.^[6]They begin to developgap junctions,enabling them to develop in an integrated way and co-ordinate their response to physiological signals and environmental cues.^[7]

When the cells number around sixteen, the solid sphere of cells within the zona pellucida is referred to as amorula.^[8]

Blastulation

Blastocyst with aninner cell massandtrophoblast

Cleavage itself is the first stage inblastulation,the process of forming theblastocyst.Cells differentiate into an outer layer of cells called thetrophoblast,and aninner cell mass.With further compaction the individual outer blastomeres, the trophoblasts, become indistinguishable. They are still enclosed within thezona 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 becomeembryoblastsandpolariseat one end. They close together and formgap junctions,which facilitate cellular communication. This polarisation leaves a cavity, theblastocoel,creating a structure that is now termed the blastocyst. (In animals other than mammals, this is called theblastula).

The trophoblasts secrete fluid into the blastocoel. The resulting increase in size of the blastocyst causes it tohatchthrough the zona pellucida, which then disintegrates.^[5]This process is calledzona hatchingand it takes place on the sixth day of embryo development, immediately before the implantation process. The hatching of the human embryo is supported by proteases secreted by the cells of the blastocyst, which digest proteins of the zona pellucida, giving rise to a hole. Then, due to the rhythmic expansion and contractions of the blastocyst, an increase of the pressure inside the blastocyst itself occurs, the hole expands and finally the blastocyst can emerge from this rigid envelope.

The inner cell mass will give rise to thepre-embryo,^[9]theamnion,yolk sacandallantois,while the fetal part of theplacentawill form from the outer trophoblast layer. The embryo plus itsmembranesis called theconceptus,and by this stage the conceptus has reached theuterus.The zona pellucida ultimately disappears completely, and the now exposed cells of the trophoblast allow the blastocyst to attach itself to theendometrium,where it willimplant. The formation of thehypoblastandepiblast,which are the two main layers of the bilaminar germ disc, occurs at the beginning of the second week.^[10]Both the embryoblast and the trophoblast will turn into two sub-layers.^[11]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.^[10]^[11]

The trophoblast will also develop two sub-layers: thecytotrophoblast,which is in front of thesyncytiotrophoblast,which in turn lies within theendometrium.^[10]Next, another layer called theexocoelomic membrane or Heuser's membranewill appear and surround the cytotrophoblast, as well as the primitive yolk sac.^[11]The syncytiotrophoblast will grow and will enter a phase called lacunar stage, in which some vacuoles will appear and be filled by blood in the following days.^[10]^[11]The development of the yolk sac starts with thehypoblasticflat cells that form the exocoelomic membrane, which will coat the inner part of the cytotrophoblast to form the primitive yolk sac. An erosion of the endothelial lining of the maternal capillaries by the syncytiotrophoblastic cells results in the formation of the maternal sinusoids from where the blood will begin to penetrate and flow into and through the trophoblastic lacunae to give rise to the uteroplacental circulation.^[12]^[13]Subsequently, new cells derived from yolk sac will be established between trophoblast and exocoelomic membrane and will give rise to extra-embryonicmesoderm,which will form thechorionic cavity.^[11]

At the end of the second week of development, some cells of the trophoblast penetrate and form rounded columns into the syncytiotrophoblast. These columns are known asprimary villi.At the same time, other migrating cells form into the exocoelomic cavity a new cavity named the secondary or definitive yolk sac, smaller than the primitive yolk sac.^[11]^[12]

Implantation

Trophoblast differentiation

Afterovulation,theendometrial liningbecomes transformed into a secretory lining in preparation of accepting the embryo. It becomes thickened, with itssecretory glandsbecoming elongated, and is increasinglyvascular.This lining of the uterine cavity (or womb) is now known as thedecidua,and it produces a great number of largedecidual cellsin its increased interglandular tissue. The blastomeres in the blastocyst are arranged into an outer layer called thetrophoblast.The trophoblast then differentiates into an inner layer, thecytotrophoblast,and an outer layer, thesyncytiotrophoblast.The cytotrophoblast containscuboidal epithelial cellsand is the source ofdividing cells,and the syncytiotrophoblast is asyncytiallayer without cell boundaries.

The syncytiotrophoblast implants the blastocyst in the decidualepitheliumby projections ofchorionic villi,forming the embryonic part of the placenta. The placenta develops once the blastocyst is implanted, connecting the embryo to the uterine wall. The decidua here is termed the decidua basalis; it lies between the blastocyst and themyometriumand forms the maternal part of theplacenta.The implantation is assisted byhydrolytic enzymesthat erode theepithelium.Thesyncytiotrophoblastalso produceshuman chorionic gonadotropin,ahormonethat stimulates the release ofprogesteronefrom thecorpus luteum.Progesterone enriches the uterus with a thick lining of blood vessels and capillaries so that it can oxygenate and sustain the developing embryo. The uterus liberates sugar from storedglycogenfrom its cells to nourish theembryo.^[14]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.^[11]^[15] Arteries in the decidua are remodelled to increase the maternal blood flow into the intervillous spaces of the placenta, allowinggas exchangeand 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 embryonicstem cells,which arepluripotentand 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 anembryonic discof two layers, the upper layer is called theepiblastand the lower layer, thehypoblast.The disc is stretched between what will become theamniotic cavityand 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 fromamnioblastsdeveloped 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 anextracellular matrixalong the way. These hypoblast cells and extracellular matrix are calledHeuser'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 thechorionic cavity(extraembryonic coelom).

Gastrulation

Histogenesisof the three germ layers

Artificially colored –gestational sac,yolk sacandembryo(measuring 3 mm at five weeks)

Embryo attached to placenta in amniotic cavity

Theprimitive streak,a linear collection of cells formed by the migrating epiblast, appears, and this marks the beginning ofgastrulation,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 establishesbilateral symmetry.Aprimitive node(or primitive knot) forms in front of the primitive streak which is the organiser ofneurulation.Aprimitive pitforms as a depression in the centre of the primitive node which connects to thenotochordwhich lies directly underneath. The node has arisen from epiblasts of the amniotic cavity floor, and it is this node that induces the formation of theneural platewhich 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 calledingression,which leads to the formation of the mesoderm takes place. This ingression sees the cells from the epiblast move into the primitive streak in anepithelial-mesenchymal transition;epithelial cells become mesenchymal stem cells,multipotent stromalcells that candifferentiateinto various cell types. The hypoblast is pushed out of the way and goes on to form theamnion.The epiblast keeps moving and forms a second layer, the mesoderm. The epiblast has now differentiated into the threegerm layersof the embryo, so that the bilaminar disc is now a trilaminar disc, thegastrula.

The three germ layers are theectoderm,mesodermandendoderm,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 ofsomitogenesis,histogenesisandorganogenesis.^[16]The embryonic endoderm is formed byinvaginationof 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.^[11]^[15]The upper layer of ectoderm will give rise to the outermost layer of skin, central and peripheralnervous systems,eyes,inner ear,and manyconnective tissues.^[17]The middle layer of mesoderm will give rise to the heart and the beginning of thecirculatory systemas well as thebones,musclesandkidneys.The inner layer of endoderm will serve as the starting point for the development of thelungs,intestine,thyroid,pancreasandbladder.

Following ingression, ablastoporedevelops where the cells have ingressed, in one side of the embryo and it deepens to become thearchenteron,the first formative stage of thegut.As in alldeuterostomes,the blastopore becomes theanuswhilst 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 ofneurulationcan begin.

Neurulation

Neural plate

Neural tube development

Following gastrulation, the ectoderm gives rise to epithelial andneural tissue,and the gastrula is now referred to as theneurula.Theneural platethat has formed as a thickened plate from the ectoderm, continues to broaden and its ends start to fold upwards asneural folds.Neurulationrefers to this folding process whereby the neural plate is transformed into theneural tube,and this takes place during the fourth week. They fold, along a shallowneural groovewhich 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 theneural crest.The cells that migrate through the most cranial part of the primitive line form theparaxial mesoderm,which will give rise to thesomitomeresthat in the process ofsomitogenesiswill differentiate intosomitesthat will form thesclerotomes,thesyndetomes,^[18]themyotomesand thedermatomesto formcartilageandbone,tendons,dermis(skin), andmuscle.The intermediate mesoderm gives rise to theurogenital tractand consists of cells that migrate from the middle region of the primitive line. Other cells migrate through thecaudalpart of the primitive line and form the lateral mesoderm, and those cells migrating by the most caudal part contribute to the extraembryonic mesoderm.^[11]^[15]

The embryonic disc begins flat and round, but eventually elongates to have a wider cephalic part and narrow-shaped caudal end.^[10]At the beginning, the primitive line extends incephalicdirection and 18 days after fertilization returns caudally until it disappears. In the cephalic portion, the germ layer shows specific differentiation at the beginning of the fourth week, while in the caudal portion it occurs at the end of the fourth week.^[11]Cranial and caudalneuroporesbecome progressively smaller until they close completely (by day 26) forming theneural tube.^[19]

Development of organs and organ systems

Nine-week-old human embryo from anectopic pregnancy

Organogenesisis the development of theorgansthat 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 manyorgan systemsof the body.

Blood

Haematopoietic stem cellsthat give rise to all theblood cellsdevelop from the mesoderm. The development ofblood formationtakes place in clusters of blood cells, known asblood islands,in theyolk sac.Blood islands develop outside the embryo, on the umbilical vesicle, allantois, connecting stalk, and chorion, from mesodermalhemangioblasts.

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 intoangioblasts,the precursors to the blood vessels.^[20]

Heart and circulatory system

The heart is the first functional organ to develop and starts to beat and pump blood at around 22 days.^[21]Cardiacmyoblastsandblood islandsin thesplanchnopleuric mesenchymeon each side of theneural plategive rise to thecardiogenic region.^[11]^: 165This is a horseshoe-shaped area near to the head of the embryo. By day 19, followingcell signalling,two strands begin to form as tubes in this region, as a lumen develops within them. These twoendocardial tubesgrow and by day 21 have migrated towards each other and fused to form a single primitive heart tube, thetubular heart.This is enabled by the folding of the embryo which pushes the tubes into thethoracic cavity.^[22]

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 intoangioblaststhat 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 ofangiogenesis.^[22]Following vasculogenesis and the development of an early vasculature, a stage ofvascular remodellingtakes place.

The tubular heart quickly forms five distinct regions. From head to tail, these are theinfundibulum,bulbus cordis,primitive ventricle,primitive atrium,and thesinus venosus.Initially, all venous blood flows into the sinus venosus, and is propelled from tail to head to thetruncus arteriosus.This will divide to form theaortaandpulmonary artery;the bulbus cordis will develop into the right (primitive) ventricle; the primitive ventricle will form the left ventricle; the primitive atrium will become the front parts of the left and right atria and their appendages, and the sinus venosus will develop into the posterior part of the rightatrium,thesinoatrial nodeand thecoronary sinus.^[21]

Cardiac looping begins to shape the heart as one of the processes ofmorphogenesis,and this completes by the end of the fourth week.Programmed cell death(apoptosis) at the joining surfaces enables fusion to take place.^[22] In the middle of the fourth week, the sinus venosus receives blood from the three major veins: thevitelline,theumbilicaland thecommon cardinal veins.

During the first two months of development, theinteratrial septumbegins to form. This septum divides theprimitive atriuminto a right and a leftatrium.Firstly it starts as a crescent-shaped piece of tissue which grows downwards as theseptum primum.The crescent shape prevents the complete closure of the atria allowing blood to be shunted from the right to the left atrium through the opening known as theostium primum.This closes with further development of the system but before it does, a second opening (theostium secundum) begins to form in the upper atrium enabling the continued shunting of blood.^[22]

A second septum (theseptum secundum) begins to form to the right of the septum primum. This also leaves a small opening, theforamen ovalewhich is continuous with the previous opening of the ostium secundum. The septum primum is reduced to a small flap that acts as the valve of the foramen ovale and this remains until its closure at birth. Between theventriclestheseptum inferiusalso forms which develops into the muscularinterventricular septum.^[22]

Digestive system

The digestive system starts to develop from the third week and by the twelfth week, the organs have correctly positioned themselves.

Respiratory system

The respiratory system develops from thelung 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 mainbronchi.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 thelarynxoriginates from thelung bud,its cartilages and muscles originate from the fourth and sixthpharyngeal arches.^[23]

Urinary system

Kidneys

Three differentkidneysystems form in the developing embryo: thepronephros,themesonephrosand themetanephros.Only the metanephros develops into the permanent kidney. All three are derived from theintermediate mesoderm.

Pronephros

Thepronephrosderives from the intermediate mesoderm in the cervical region. It is not functional and degenerates before the end of the fourth week.

Mesonephros

Themesonephrosderives from intermediate mesoderm in the upper thoracic to upper lumbar segments. Excretory tubules are formed and enter themesonephric duct,which ends in thecloaca.The mesonephric duct atrophies in females, but participate indevelopment of the reproductive systemin males.

Metanephros

The metanephros appears in the fifth week of development. An outgrowth of the mesonephric duct, theureteric bud,penetrates metanephric tissue to form the primitiverenal pelvis,renal calycesandrenal pyramids.Theureteris also formed.

Bladder and urethra

Between the fourth and seventh weeks of development, theurorectal septumdivides thecloacainto theurogenital sinusand theanal canal.The upper part of the urogenital sinus forms thebladder,while the lower part forms theurethra.^[23]

Reproductive system

Integumentary system

The superficial layer of theskin,theepidermis,is derived from theectoderm.The deeper layer, thedermis,is derived frommesenchyme.

The formation of the epidermis begins in the second month of development and it acquires its definitive arrangement at the end of the fourth month. The ectoderm divides to form a flat layer of cells on the surface known as the periderm. Further division forms the individuallayers of the epidermis.

The mesenchyme that will form the dermis is derived from three sources:

The mesenchyme that forms the dermis in the limbs and body wall derives from thelateral plate mesoderm
The mesenchyme that forms the dermis in the back derives fromparaxial mesoderm
The mesenchyme that forms the dermis in the face and neck derives fromneural crest cells^[23]

Nervous system

Development of brain in eight-week-old embryo

Late in the fourth week, the superior part of the neural tube bends ventrally as thecephalic flexureat the level of the futuremidbrain—themesencephalon.^[24]Above the mesencephalon is theprosencephalon(future forebrain) and beneath it is therhombencephalon(future hindbrain).

Cranial neural crestcells migrate to thepharyngeal archesasneural stem cells,where they develop in the process ofneurogenesisintoneurons.

Theoptical vesicle(which eventually becomes theoptic nerve,retinaandiris) forms at the basal plate of the prosencephalon. Thealar plateof the prosencephalon expands to form the cerebral hemispheres (the telencephalon) whilst itsbasal platebecomes 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 theface and neck develop.

Ears

Theinner ear,middle earandouter earhave distinct embryological origins.

Inner ear

At about 22 days into development, theectodermon each side of therhombencephalonthickens to formotic placodes.These placodesinvaginateto formotic pits,and thenotic vesicles.The otic vesicles then form ventral and dorsal components.

The ventral component forms thesacculeand thecochlear duct.In the sixth week of development the cochlear duct emerges and penetrates the surroundingmesenchyme,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 narrowductus reuniens.

The dorsal component forms theutricleandsemicircular canals.

Middle ear

Thefirst pharyngeal pouchlengthens and expands to form thetubotympanic recess.This recess differentiates to form most of thetympanic cavityof themiddle ear,and all of theEustachian or auditory tube.The narrow auditory tube connects the tympanic cavity to thepharynx.^[25]

Thebonesof the middle ear, theossicles,derive from the cartilages of thepharyngeal arches.Themalleusandincusderive from the cartilage of thefirst pharyngeal arch,whereas thestapesderives from the cartilage of thesecond pharyngeal arch.

Outer ear

Theexternal auditory meatusdevelops from the dorsal portion of the firstpharyngeal cleft.Six auricular hillocks, which are mesenchymal proliferations at the dorsal aspects of the first and second pharyngeal arches, form theauricleof the ear.^[23]

Eyes

The eyes begin to develop from the third week to the tenth week.

Movements of embryo at nine weeks gestational age

Limbs

At the end of the fourth weeklimb developmentbegins.Limb budsappear on the ventrolateral aspect of the body. They consist of an outer layer ofectodermand an inner part consisting ofmesenchymewhich is derived from the parietal layer oflateral plate mesoderm.Ectodermal cells at the distal end of the buds form theapical ectodermal ridge,which creates an area of rapidly proliferating mesenchymal cells known as theprogress zone.Cartilage(some of which ultimately becomesbone) and muscle develop from the mesenchyme.^[23]

Clinical significance

Toxic exposures in the embryonic period can be the cause of majorcongenital 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 thedifferent cell typesin the developing embryo. Thiscell potencymeans 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 aspreimplantation genetic diagnosis,whereby a small number of cells from the preimplantation embryo created byIVF,can be removed bybiopsyand subjected to genetic diagnosis. This allows embryos that are not affected by defined genetic diseases to be selected and then transferred to the mother'suterus.

Sacrococcygeal teratomas,tumours formed from different types of tissue, that can form, are thought to be related to primitive streak remnants, which ordinarily disappear.^[10]^[11]^[13]

First arch syndromesarecongenital disordersof facial deformities, caused by the failure of neural crest cells to migrate to the first pharyngeal arch.

Spina bifidaacongenital disorderis the result of the incomplete closure of the neural tube.

Vertically transmitted infectionscan be passed from the mother to the unborn child at any stage of itsdevelopment.

Hypoxiaa condition of inadequate oxygen supply can be a serious consequence of apretermor premature birth.

Additional images

Representing different stages of embryogenesis
Early stage of the gastrulation process
Phase of the gastrulation process
Top of the form of the embryo
Establishment of embryo medium
Spinal cord at five weeks
Head and neck at 32 days

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^^a ^b ^c ^d ^eLarsen, W J (2001).Human Embryology(3rd ed.). Elsevier. pp. 170–190.ISBN 0-443-06583-7.
^^a ^b ^c ^d ^eSadler, Thomas W. (2012).Langman's medical embryology.Langman, Jan. (12th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins.ISBN 9781451113426.OCLC 732776409.
^Zhou, Yi; Song, Hongjun; Ming, Guo-Li (2023-07-28)."Genetics of human brain development".Nature Reviews. Genetics.doi:10.1038/s41576-023-00626-5.ISSN 1471-0064.PMC10926850.PMID 37507490.
^Larsen's human embryology(5. ed.). Philadelphia, Pa: Elsevier, Churchill Livingstone. 2015. p. 485.ISBN 9781455706846.

External links

[1] "germinal stage".Mosby's Medical Dictionary, 8th edition.Elsevier.Retrieved6 October2013.

[Marlow-2] Marlow, Florence L (2020).Maternal Effect Genes in Development.Academic Press. p. 124.ISBN 978-0128152218.

[Singh-3] Singh, Vishram (2013).Textbook of Clinical Embryology – E-book.Elsevier Health Sciences. p. 35.ISBN 978-8131236208.

[Standring-4] Standring, Susan (2015).Gray's Anatomy E-Book: The Anatomical Basis of Clinical Practice.Elsevier Health Sciences. p. 163.ISBN 978-0702068515.

[Cambridge_University_Press-5] Forgács, G.; Newman, Stuart A. (2005)."Cleavage and blastula formation".Biological physics of the developing embryo.Cambridge University Press. p. 27.ISBN 978-0-521-78337-8.

[Standring2-6] Standring, Susan (2015).Gray's Anatomy E-Book: The Anatomical Basis of Clinical Practice.Elsevier Health Sciences. p. 166.ISBN 978-0702068515.

[BrisonSturmey2014-7] Brison, D. R.; Sturmey, R. G.; Leese, H. J. (2014)."Metabolic heterogeneity during preimplantation development: the missing link?".Human Reproduction Update.20(5): 632–640.doi:10.1093/humupd/dmu018.ISSN 1355-4786.PMID 24795173.

[8] Boklage, Charles E. (2009).How New Humans Are Made: Cells and Embryos, Twins and Chimeras, Left and Right, Mind/Self/Soul, Sex, and Schizophrenia.World Scientific. p. 217.ISBN 978-981-283-513-0.

[opentext-9] "28.2 Embryonic Development – Anatomy and Physiology".opentextbc.ca.

[Carlson-10] Carlson, Bruce M. (1999) [1t. Pub. 1997]. "Chapter 4: Formation of germ layers and initial derivatives".Human Embryology & Developmental Biology.Mosby, Inc. pp. 62–68.ISBN 0-8151-1458-3.

[Sadler-11] ^^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^lSadler, T.W.; Langman, Jan (2012) [1st. Pub. 2001]. "Chapter 3: Primera semana del desarrollo: de la ovulación a la implantación". In Seigafuse, sonya (ed.).Langman, Embriología médica.Lippincott Williams & Wilkins, Wolters Kluwer. pp. 29–42.ISBN 978-84-15419-83-9.

[Moore-12] Moore, Keith L.; Persaud, V.N. (2003) [1t. Pub. 1996]. "Chapter 3: Formation of the bilaminar embryonic disc: second week".The Developing Human, Clinically Oriented Embryology.W B Saunders Co. pp. 47–51.ISBN 0-7216-9412-8.

[Larsen-13] Larsen, William J.; Sherman, Lawrence S.; Potter, S. Steven; Scott, William J. (2001) [1t. Pub. 1998]. "Chapter 2: Bilaminar embryonic disc development and establishment of the uteroplacental circulation".Human Embryology.Churchill Livingstone. pp. 37–45.ISBN 0-443-06583-7.

[14] Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006).Biology: Exploring Life.Boston: Pearson Prentice Hall.ISBN 0-13-250882-6.

[Smith-15] Smith Agreda, Víctor; Ferrés Torres, Elvira; Montesinos Castro-Girona, Manuel (1992). "Chapter 5: Organización del desarrollo: Fase de germinación".Manual de embriología y anatomía general.Universitat de València. pp. 72–85.ISBN 84-370-1006-3.

[16] Schünke, Michael; Ross, Lawrence M.; Schulte, Erik; Schumacher, Udo; Lamperti, Edward D. (2006).Thieme Atlas of Anatomy: General Anatomy and Musculoskeletal System.Thieme.ISBN 978-3-13-142081-7.

[D-17] "Pregnancy week by week".Retrieved28 July2010.

[pmid12705871-18] Brent AE, Schweitzer R, Tabin CJ (April 2003)."A somitic compartment of tendon progenitors".Cell.113(2): 235–48.doi:10.1016/S0092-8674(03)00268-X.PMID 12705871.S2CID 16291509.

[19] Larsen, W J (2001).Human Embryology(3rd ed.). Elsevier. p. 87.ISBN 0-443-06583-7.

[LME-20] Sadler, T.W. (2010).Langman's Medical Embryology(11th ed.). Baltimore: Lippincott Williams &Wilkins. pp. 79–81.ISBN 9780781790697.

[Anatomy_&_physiology-21] Betts, J. Gordon (2013).Anatomy & physiology.pp. 787–846.ISBN 978-1938168130.

[Human_Embryology-22] Larsen, W J (2001).Human Embryology(3rd ed.). Elsevier. pp. 170–190.ISBN 0-443-06583-7.

[:0-23] Sadler, Thomas W. (2012).Langman's medical embryology.Langman, Jan. (12th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins.ISBN 9781451113426.OCLC 732776409.

[24] Zhou, Yi; Song, Hongjun; Ming, Guo-Li (2023-07-28)."Genetics of human brain development".Nature Reviews. Genetics.doi:10.1038/s41576-023-00626-5.ISSN 1471-0064.PMC10926850.PMID 37507490.

[Larsen2015-25] Larsen's human embryology(5. ed.). Philadelphia, Pa: Elsevier, Churchill Livingstone. 2015. p. 485.ISBN 9781455706846.

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