Embryology 4 - Gastrulation PDF

During the 3rd week the 2 embryo layers become 3 through gastrulation. Gastrulation extends also to the beginning of the fourth week. The three germinal layers will then form the different tissues. The three layers are:...

During the 3rd week the 2 embryo layers become 3 through gastrulation. Gastrulation extends also to the beginning of the fourth week. The three germinal layers will then form the different tissues. The three layers are: Endoderm Mesoderm Ectoderm CLINICAL DROPs: Sirenomielia —> the babies have fused legs and sometimes fused internal organs Conjoined twins —> twins that are not separated in certain parts of the body Situs inversus —> organs in the opposite sites of where they should be (can lead to pathologies) All of these problems occur during gastrulation VIDEO ON HOW THE LAYERS BECOME THREE The embryo at this point is a disk. The dorsal pole (epiblast) starts presenting an invagination called primitive streak. The primitive streak is divided into the primitive node (which has a hole called primitive pit) and the primitive groove. This marks the start of gastrulation. The streak is formed because some cells of the epiblast start to dedifferentiate and migrate towards that region. Some of them form the node and pit while others form the groove. Thanks to the appearance of the streak we can now recognise a caudal (streak) and a cranial (no streak) part in the embryo + a dorsal and a ventral one (already established by the epiblast and hypoblast) + a right/left one (taking the streak as a reference) + a medial (close to the streak) and lateral one (sides of the streak) Formation of the primitive streak—> migration of cells of the epiblast towards the midline guided by factors like FGF 8 (fibroblast growth factor 8) and creation of the streak by invagination in the epiblast. This is possible thanks to the process of epithelio-mesenchymal transition (EMT) —> cells dedifferentiate to express characteristics that allow them to move (different shape and size, from cell-to-cell adhesion to cell-to-substrate adhesion and a cytoskeletal reorganisation) Hyaluronic acid provides a fluid environment through which cells can migrate First wave of migration (14-15 days) —> creation of the definitive endoderm (the hypoblast is replaced) Second wave of migration (16 days) —> creation of the mesoderm (between the definite endoderm and what remains of the epiblast, which will be called ectoderm) Epithelio-mesenchymal transition (EMT) —> dedifferentiation of epithelial cells. The factor Snail is a zinc finger transcription factor involved in EMT. Snail binds with certain regions of the DNA and is able to repress some factors like desmoplakin (expression of hemidesmosomes), cytokeratine (cytoskeleton of epithelia cells) and E-cadherin (involved in baso-lateral adhesion of epithelia cell). Basically, Snail represses the epithelial features and favours the development of the typical features of undifferentiated cells, like for example the expression of vimentin and fibronectin. Snail is activated by other factors. Snail activated in malignancy —> cells lose their invasive very differentiated features and start to break the basement membrane to proliferate. Mesenchymal cells are undifferentiated multi potent stem cells that are able to give rise to cells of the connective tissue (like osteoblasts, chondroblasts, fibroblasts and pre adipocytes) Mesenchymal cells produce an ECM with mainly ground substance rich in hyaluronic acid. Mesenchymal cells in humans are present in small quantities as part of the loose connective tissue (umbilical cord, bone marrow and adipose tissue). Adult mesenchymal cells serve to produce new blood vessels The first layer to form is the ENDODERM. The primitive endoderm was forming the outer layer of the yolk sack (hypoblast). The endoderm will contribute to the formation of the mucosa of the intestinal tube, the pancreas, the respiratory tract, the liver, the urinary bladder, the pharynx and the thyroid  mesoderm aivionesins The second layer to form is the MESODERM The mesoderm is subdivided into 3 different compartments —> paraxial mesoderm (dermis, ribs, some muscles…), lateral mesoderm (cardiac mesoderm)and intermediate mesoderm The oropharyngeal membrane (rostral) and the cloacal membrane (caudal) are very thin spaces where the mesoderm doesn’t spread. The oropharyngeal membrane is the place where the digestive tract will develop, while the cloacal membrane will be divided into an anterior part and a posterior part and there the future anal canal and urinary tract will open. oropharyngeal membrane g primitive streak the of erection moon spreading ofthe mesoderm invaginating Gaue membrane  Subdivisions of the mesoderm: genitive Prechordal plate (or meso-endodermal structure) —> group of cells associated with a region called anterior visceral endoderm. It is formed in the rostral region of the embryo caudally to the oropharyngeal membrane. It will help develop the head of the embryo and the rostral portion of the nervous system. It has an inductive and patterning role in the territory of the head. Notochord —> tubular structure elongating rostral to the primitive node and caudal to the prechordal plate. It is important because it guides the development of some structures in the early embryo (axial skeleton and neural plate). The notochord produces things that induce cells to become something else and to acquire a definite position (inductive and patterning role). Essential role in vertebrate development Paraxial mesoderm —> develops on the side of the notochord Intermediate mesoderm —> develops on the sides of the paraxial mesoderm Lateral plate mesoderm —> develops more laterally than the intermediate mesoderm Extraembryonic mesoderm —> in continuity with the intraembryonic mesoderm, it will form the chorionic cavity Primitive heart field —> develops on the rostral part of the oropharyngeal membrane, it is where the heart will form The notochord is elongating towards the prechordal plate while the primitive streak is shortening. Initially the notochord is a tubular purple structure (hollow, with lumen inside). This tubular structure then fuses with the endoderm and then pinches off again becoming a rod (filled with cells, no lumen inside). This takes place while the notochord is elongating This allows communication between the vitelline sack and the amniotic sack  These streaks will become the neural plate Malignant cancers that develop from remnants of the notochord —> chordomas —> remnants pieces of the notochord that stay silent for decades and grow slowly —> they can develop at the base of the skull or in the vertebral column. They are already large when discovered and they cause a compression of the brain or of spinal structures. Symptoms develop and worsen over time (symptoms can include headache and double vision). Paraxial mesoderm —> it develops in the head and trunk region of the embryo. In the region of the trunk the paraxial mesoderm will undergo somitogenesis, forming the somites. In the head there will be no segmentation and the head mesenchyme will be formed; there will be a contribution from the neural crest and from the prechordal plate The intermediate mesoderm and the lateral plate mesoderm only form in the trunk part of the embryo. The kidneys, gonads, urinary system and part of the genital tract will originate from the intermediate mesoderm The lateral plate mesoderm will split into the splanchnic mesoderm (ventral) and the somatic mesoderm (dorsal, lining of the body cavities). This separation will lead to the formation of two cavities called intrambryonic coelom. The intrambryonic mesoderm of the lateral plate is in continuity with the extraembryonic mesoderm, which surrounds the yolk sack and the amniotic sack Primitive heart field —> during the migrating process some cells migrate rostral to the oropharyngeal membrane forming a field of mesenchyme called the primitive heart field. Cells migrate in specific parts of the cardiac crescent (called like this because it resembles a moon) because they already “know” what part of the heart they will become. Derivates of the ECTODERM —> outer epithelium of the body (epidermis) and neural plate (future neural tube). The neural crest also originates from the ectoderm and it can be considered as a 4th germinal layer Part of the ectodermal cells that will become cells of the neural plate will differentiate into a structure called “neural crest” —> very sophisticated bunch of cells that can migrate in the body after the formation of the neural tube and give rise to different tissues. The neural crest can be considered a sort of fourth layer. From the neural crest all the peripheral nervous system will be originated. Melanocytes, cornea, teeth and heart also derive from the neural crest. Formation of the neural crest —> the prechordal plate and the notochord start to send signals to the ectoderm and as a result cells of the ectoderm change characteristics and destination. The epithelia starts getting thicker thus forming the neural plate biggerintherostral site pattern The formation of the neural plate takes the name of NEURULATION In the midline do the neural plane there is a groove (indentation) called neural groove. Formation of the neural tube —> at the boundaries between the neural plate and the rest of the ectoderm there is the formation of the neural crest. The groove deepens and the two sides lift and conjoin forming the neural tube. The ectoderm then closes on the tube. The neural crests(green) then detach. The neural tube will form the central nervous tissue while the crests need to migrate away. The closing starts from the 4th somite and proceeds both rostrally and caudally, until just two pores are left open on the two ends —> the rostral neuropore remains open for 24 days while the caudal neuropore remains open for 26 days. After that they close. The non closure of the rostral neuropore can give rise to anencephalia (lack of development of the brain, the embryo dies) while the non clause of the caudal neuropore can give rise to spina bifida.  sectoranea more f sustrostrae inhibitsthisigwayne a aureus produces mayetheraareeopino in my moderates caraceportion bone m orphogenetic Result of the action of the notochord and prechordal plate: INDUCTION —> induction of the differentiation COMMITMENT —> some cells become neurons, some glial cells… (no coming back) REGIONALISATION —> patterning Nodal is also a signalling associated to tumour progression (read articles on the slides) Neurocristopathies —> problems with migration and proliferation of neural crest cells in the embryo Gastrulation takes place from the rostral part to the caudal part. In the cephalon region (rostral) the layers start differentiating in the 3rd week while in the caudal region they begin in the 4th week Caudal dysplasia —> problems in the caudal structure (due to environmental factors and mutations) Sirenomielia happens due to an insufficient development of the caudal mesoderm. It affects lower limbs, the urogenital system and the lumbar vertebrae risks  Ethanol can be a teratogen —> it can alter the genes expressed on the midline (like Hox genes), which then lead to the failure of activation of the sonic hedgehog (SHH) pathway, important for development. This can lead to cyclopia and holoprosencephaly Holoprosencephaly —> non development of the rostral part of the brain. Sonic hedgehog pathway (Shh) is very important in development (organogenesis) and in adults (homeostasis and regeneration) for intercellular communication. It can be disrupted NoCENTRAL when cancers proliferate. Shh relies a lot on the primary cilium Doubet (single non motile cilium present in most cells, important for cell signalling during development, the majority of signalling pathways in vertebrates function through it, it is a sort of cell’s antenna). There are three Hh proteins (Sonic, Indian and Desert) When the primary cilium doesn’t develop properly diseases called ciliopathies may develop Gastrulation ends with the formation of the tail bud in the caudal part (remnants of the primitive streak). By day 20 the remnants of the primitive streak swell and form the tail bud (or caudal eminence). Secondary neurulation —> process of differentiation of the cells of the primitive streak that leads to the formation of the caudal part of the neural tube (final part of the spinal chord) and caudal somites The cells of the primitive streak undergo cavitation and then join the aments of eprimitive cells of the neural tube streaker Remnants of the primitive streak can give rise to teratomas —> sacrococcygeal teratomas —> they’re the most common tumour in childhood, they can become malignant in infancy and they need to be removed before the age of 6 months The pluripotency of the cells of the embryo decreases over development as the cells start taking different pathways of specialisation  The rostrocaudal axis is established with the formation of the primitive streak (nodal concentrated in the caudal part because it is inhibited in the rostral and consequent formation of the primitive streak). Hox genes have a crucial role in the activation and repression of other genes (like Nodal, Lefty and Cerberus), wedecreased thus controlling the rostro-to-caudal patterning. The same mechanism takes place in fruitflies (rosophila) are weincreased morpho gens The dorso-ventral organisation is induced by the unequal concentration of morphogens in the mesoderm. When the C embryo folds the mesoderm that was most medial (in the middle) becomes dorsal and the mesoderm that was most lateral (on the sides) becomes ventral How does the symmetry of the embryo get broken down? (some organs are more on the left while some others are more on the right). This is due to the difference in concentration of some molecules in the left/right part of the embryo In mammalian embryos the current earliest known manifestation of asymmetry involves the beating of monocilia in the primitive node (the cells in the periphery of the node have a non motile cilia). Two models —> NVP model: The cilium bends towards the left and establishes a right-to-left flow of membrane-sheathed vesicles carrying morphogens.. Mechanosensory model of nodal flow: Left-right dynein (Lrd) bends the cilia and consequently fluid currents degenerate. When the concentration symmetry is broken the asymmetric cascade of gene expression is triggered —> symmetry breaking molecules (FGF8) and expression of nodal and lefty-1 (prevents molecules from going back to the right part) During the sweeping process serotonin (5HT) is more concentrated on the left while MAO (monoamine oxidase, inhibits serotonin) is more concentrated in the right side. If the mother uses antidepressants such as MAO inhibitors problems will be caused to the embryo (too much serotonin will go the right) concentration ew mo eees Situs inversus totalis —> cilia move the other way round and the whole body develops symmetrically to what it should be. If all the organs are inverted there are no problems Kartagener syndrome —> situs inversus + immotile respiratory cilia and sperm flagella. This is caused by mutations in dynein genes and deficiency in ciliary dynein arms. These people are sterile (non motile flagellum of spermatozoa/cilia of the uterine tube) and may have problems in the respiratory tract due to an accumulation of mucous (which isn’t moved away by cilia)