Encephalization quotient

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Encephalization_quotient

Encephalization quotient (EQ), encephalization level (EL), or just encephalization is a relative brain size measure that is defined as the ratio between observed and predicted brain mass for an animal of a given size, based on nonlinear regression on a range of reference species. It has been used as a proxy for intelligence and thus as a possible way of comparing the intelligence levels of different species. For this purpose, it is a more refined measurement than the raw brain-to-body mass ratio, as it takes into account allometric effects. Expressed as a formula, the relationship has been developed for mammals and may not yield relevant results when applied outside this group.

Perspective on intelligence measures

Encephalization quotient was developed in an attempt to provide a way of correlating an animal's physical characteristics with perceived intelligence. It improved on the previous attempt, brain-to-body mass ratio, so it has persisted. Subsequent work, notably Roth, found EQ to be flawed and suggested brain size was a better predictor, but that has problems as well.

Currently the best predictor for intelligence across all animals is forebrain neuron count. This was not seen earlier because neuron counts were previously inaccurate for most animals. For example, human brain neuron count was given as 100 billion for decades before Herculano-Houzel found a more reliable method of counting brain cells.

It could have been anticipated that EQ might be superseded because of both the number of exceptions and the growing complexity of the formulae it used. (See the rest of this article.) The simplicity of counting neurons has replaced it. The concept in EQ of comparing the brain capacity exceeding that required for body sense and motor activity may yet live on to provide an even better prediction of intelligence, but that work has not been done yet.

Variance in brain sizes

Body size accounts for 80–90% of the variance in brain size, between species, and a relationship described by an allometric equation: the regression of the logarithms of brain size on body size. The distance of a species from the regression line is a measure of its encephalization. The scales are logarithmic, distance, or residual, is an encephalization quotient (EQ), the ratio of actual brain size to expected brain size. Encephalization is a characteristic of a species.

Rules for brain size relates to the number brain neurons have varied in evolution, then not all mammalian brains are necessarily built as larger or smaller versions of a same plan, with proportionately larger or smaller numbers of neurons. Similarly sized brains, such as a cow or chimpanzee, might in that scenario contain very different numbers of neurons, just as a very large cetacean brain might contain fewer neurons than a gorilla brain. Size comparison between the human brain and non-primate brains, larger or smaller, might simply be inadequate and uninformative – and our view of the human brain as outlier, a special oddity, may have been based on the mistaken assumption that all brains are made the same (Herculano-Houzel, 2012).

Limitations and possible improvements over EQ

There is a distinction between brain parts that are necessary for the maintenance of the body and those that are associated with improved cognitive functions. These brain parts, although functionally different, all contribute to the overall weight of the brain. Jerison (1973) has for this reason considered 'extra neurons', neurons that contribute strictly to cognitive capacities, as more important indicators of intelligence than pure EQ. Gibson et al. (2001) reasoned that bigger brains generally contain more 'extra neurons' and thus are better predictors of cognitive abilities than pure EQ among primates.

Factors such as the recent evolution of the cerebral cortex and different degrees of brain folding (gyrification), which increases the surface area (and volume) of the cortex, are positively correlated to intelligence in humans.

In a meta-analysis, Deaner et al. (2007) tested absolute brain size (ABS), cortex size, cortex-to-brain ratio, EQ, and corrected relative brain size (cRBS) against global cognitive capacities. They have found that, after normalization, only ABS and neocortex size showed significant correlation to cognitive abilities. In primates, ABS, neocortex size, and Nc (the number of cortical neurons) correlated fairly well with cognitive abilities. However, there were inconsistencies found for Nc. According to the authors, these inconsistencies were the result of the faulty assumption that Nc increases linearly with the size of the cortical surface. This notion is incorrect because the assumption does not take into account the variability in cortical thickness and cortical neuron density, which should influence Nc.

According to Cairo (2011), EQ has flaws to its design when considering individual data points rather than a species as a whole. It is inherently biased given that the cranial volume of an obese and underweight individual would be roughly similar, but their body masses would be drastically different. Another difference of this nature is a lack of accounting for sexual dimorphism. For example, the female human generally has smaller cranial volume than the male; however, this does not mean that a female and male of the same body mass would have different cognitive abilities. Considering all of these flaws, EQ should not be viewed as a valid metric for intraspecies comparison.

The notion that encephalization quotient corresponds to intelligence has been disputed by Roth and Dicke (2012). They consider the absolute number of cortical neurons and neural connections as better correlates of cognitive ability. According to Roth and Dicke (2012), mammals with relatively high cortex volume and neuron packing density (NPD) are more intelligent than mammals with the same brain size. The human brain stands out from the rest of the mammalian and vertebrate taxa because of its large cortical volume and high NPD, conduction velocity, and cortical parcellation. All aspects of human intelligence are found, at least in its primitive form, in other nonhuman primates, mammals, or vertebrates, with the exception of syntactical language. Roth and Dicke consider syntactical language an "intelligence amplifier".

Brain-body size relationship

Species	Simple brain-to-body ratio (E/S)
Treeshrew	1/10
Small birds	1/12
Human	1/40
Mouse	1/40
Dolphin	1/50
Cat	1/100
Chimpanzee	1/113
Dog	1/125
Frog	1/172
Lion	1/550
Elephant	1/560
Horse	1/600
Shark	1/2496
Hippopotamus	1/2789

Brain size usually increases with body size in animals (is positively correlated), i.e. large animals usually have larger brains than smaller animals. The relationship is not linear, however. Generally, small mammals have relatively larger brains than big ones. Mice have a direct brain/body size ratio similar to humans (1/40), while elephants have a comparatively small brain/body size (1/560), despite being quite intelligent animals. Treeshrews have a brain/body mass ratio of (1/10).

Several reasons for this trend are possible, one of which is that neural cells have a relative constant size. Some brain functions, like the brain pathway responsible for a basic task like drawing breath, are basically similar in a mouse and an elephant. Thus, the same amount of brain matter can govern breathing in a large or a small body. While not all control functions are independent of body size, some are, and hence large animals need comparatively less brain than small animals. This phenomenon can be described by an equation ${\displaystyle C=E/S^{2/3},}$ where ${\displaystyle E}$ and ${\displaystyle S}$ are brain and body weights respectively, and ${\displaystyle C}$ is called the cephalization factor. To determine the value of this factor, the brain and body weights of various mammals were plotted against each other, and the curve of such formula chosen as the best fit to that data.

The cephalization factor and the subsequent encephalization quotient was developed by H. J. Jerison in the late 1960s. The formula for the curve varies, but an empirical fitting of the formula to a sample of mammals gives $${\displaystyle \frac{w(\text{brain})}{1\text{g}}=0.12{\left(\frac{w(\text{body})}{1\text{g}}\right)}^{\frac{2}{3}}=12{\left(\frac{w(\text{body})}{1\text{kg}}\right)}^{\frac{2}{3}}.}$$ As this formula is based on data from mammals, it should be applied to other animals with caution. For some of the other vertebrate classes the power of 3/4 rather than 2/3 is sometimes used, and for many groups of invertebrates the formula may give no meaningful results at all.

Calculation

Snell's equation of simple allometry is

${\displaystyle E=C{S}^r,}$

were ${\displaystyle E}$ is the weight of the brain, ${\displaystyle C}$ is the cephalization factor, ${\displaystyle S}$ is body weight, and ${\displaystyle r}$ is the exponential constant.

The "encephalization quotient" (EQ) is the coefficient ${\displaystyle C}$ in Snell's allometry equation, usually normalized with respect to a reference species. In the following table, the coefficients have been normalized with respect to the value for the cat, which is therefore attributed an EQ of 1.

Another way to calculate encephalization quotient is by dividing the actual weight of an animal's brain with its predicted weight according to Jerison's formula.

Species	Encephalization quotient (EQ)
Human	7.4–7.8
Northern right whale dolphin	5.55
Bottlenose dolphin	5.26
Orca	2.57–3.3
Chimpanzee	2.2–2.5
Raven	2.49
Domestic Pig (newborn)	2.42
Rhesus macaque	2.1
Red fox	1.92
Elephant	1.75–2.36
Raccoon	1.62
Gorilla	1.39
California sea lion	1.39
Chinchilla	1.34
Dog	1.2
Squirrel	1.1
Cat	1.00
Hyena	0.92
Horse	0.92
Elephant shrew	0.82
Brown bear	0.82
Sheep	0.8
Taurine cattle	0.52–0.59
Mouse	0.5
Rat	0.4
Rabbit	0.4
Domestic Pig (adult)	0.38
Hippopotamus	0.37
Opossum	0.2

This measurement of approximate intelligence is more accurate for mammals than for other classes and phyla of Animalia.

EQ and intelligence in mammals

Intelligence in animals is hard to establish, but the larger the brain is relative to the body, the more brain weight might be available for more complex cognitive tasks. The EQ formula, as opposed to the method of simply measuring raw brain weight or brain weight to body weight, makes for a ranking of animals that coincides better with observed complexity of behaviour. A primary reason for the use of EQ instead of a simple brain to body mass ratio is that smaller animals tend to have a higher proportional brain mass, but do not show the same indications of higher cognition as animals with a high EQ.

Grey floor

The driving theorization behind the development of EQ is that an animal of a certain size requires a minimum number of neurons for basic functioning, sometimes referred to as a grey floor. There is also a limit to how large an animal's brain can grow given its body size – due to limitations like gestation period, energetics, and the need to physically support the encephalized region throughout maturation. When normalizing a standard brain size for a group of animals, a slope can be determined to show what a species' expected brain to body mass ratio would be. Species with brain to body mass ratios below this standard are nearing the grey floor, and do not need extra grey matter. Species which fall above this standard have more grey matter than is necessary for basic functions. Presumably these extra neurons are used for higher cognitive processes.

Taxonomic trends

Mean EQ for mammals is around 1, with carnivorans, cetaceans and primates above 1, and insectivores and herbivores below. Large mammals tend to have the highest EQs of all animals, while small mammals and avians have similar EQs. This reflects two major trends. One is that brain matter is extremely costly in terms of energy needed to sustain it. Animals with nutrient rich diets tend to have higher EQs, which is necessary for the energetically costly tissue of brain matter. Not only is it metabolically demanding to grow throughout embryonic and postnatal development, it is costly to maintain as well.

Arguments have been made that some carnivores may have higher EQ's due to their relatively enriched diets, as well as the cognitive capacity required for effectively hunting prey. One example of this is brain size of a wolf; about 30% larger than a similarly sized domestic dog, potentially derivative of different needs in their respective way of life.

Dietary trends

Of the animals demonstrating the highest EQ's (see associated table), many are primarily frugivores, including apes, macaques, and proboscideans. This dietary categorization is significant to inferring the pressures which drive higher EQ's. Specifically, frugivores must utilize a complex, trichromatic map of visual space to locate and pick ripe fruits and are able to provide for the high energetic demands of increased brain mass.

Trophic level—"height" on the food chain—is yet another factor that has been correlated with EQ in mammals. Eutheria with either high AB (absolute brain-mass) or high EQ occupy positions at high trophic levels. Eutheria low on the network of food chains can only develop a high RB (relative brain-mass) so long as they have small body masses. This presents an interesting conundrum for intelligent small animals, who have behaviors radically different from intelligent large animals.

According to Steinhausen et al.(2016):

Animals with high RB [relative brain-mass] usually have (1) a short life span, (2) reach sexual maturity early, and (3) have short and frequent gestations. Moreover, males of species with high RB also have few potential sexual partners. In contrast, animals with high EQs have (1) a high number of potential sexual partners, (2) delayed sexual maturity, and (3) rare gestations with small litter sizes.

Sociality

Another factor previously thought to have great impact on brain size is sociality and flock size. This was a long-standing theory until the correlation between frugivory and EQ was shown to be more statistically significant. While no longer the predominant inference as to selection pressure for high EQ, the social brain hypothesis still has some support. For example, dogs (a social species) have a higher EQ than cats (a mostly solitary species). Animals with very large flock size and/or complex social systems consistently score high EQ, with dolphins and orcas having the highest EQ of all cetaceans, and humans with their extremely large societies and complex social life topping the list by a good margin.

Comparisons with non-mammalian animals

Birds generally have lower EQ than mammals, but parrots and particularly the corvids show remarkable complex behaviour and high learning ability. Their brains are at the high end of the bird spectrum, but low compared to mammals. Bird cell size is on the other hand generally smaller than that of mammals, which may mean more brain cells and hence synapses per volume, allowing for more complex behaviour from a smaller brain. Both bird intelligence and brain anatomy are however very different from those of mammals, making direct comparison difficult.

Manta rays have the highest EQ among fish, and either octopuses or jumping spiders have the highest among invertebrates. Despite the jumping spider having a huge brain for its size, it is minuscule in absolute terms, and humans have a much higher EQ despite having a lower raw brain-to-body weight ratio. Mean EQs for reptiles are about one tenth of those of mammals. EQ in birds (and estimated EQ in other dinosaurs) generally also falls below that of mammals, possibly due to lower thermoregulation and/or motor control demands. Estimation of brain size in Archaeopteryx (one of the oldest known ancestors of birds), shows it had an EQ well above the reptilian range, and just below that of living birds.

Biologist Stephen Jay Gould has noted that if one looks at vertebrates with very low encephalization quotients, their brains are slightly less massive than their spinal cords. Theoretically, intelligence might correlate with the absolute amount of brain an animal has after subtracting the weight of the spinal cord from the brain. This formula is useless for invertebrates because they do not have spinal cords or, in some cases, central nervous systems.

EQ in paleoneurology

Behavioral complexity in living animals can to some degree be observed directly, making the predictive power of the encephalization quotient less relevant. It is however central in paleoneurology, where the endocast of the brain cavity and estimated body weight of an animal is all one has to work from. The behavior of extinct mammals and dinosaurs is typically investigated using EQ formulas.

Encephalization quotient is also used in estimating evolution of intelligent behavior in human ancestors. This technique can help in mapping the development of behavioral complexities during human evolution. However, this technique is only limited to when there are both cranial and post-cranial remains associated with individual fossils, to allow for brain to body size comparisons. For example, remains of one Middle Pleistocene human fossil from Jinniushan province in northern China has allowed scientists to study the relationship between brain and body size using the Encephalization Quotient. Researchers obtained an EQ of 4.150 for the Jinniushan fossil, and then compared this value with preceding Middle Pleistocene estimates of EQ at 3.7770. The difference in EQ estimates has been associated with a rapid increase in encephalization in Middle Pleistocene hominins. Paleo-neurological comparisons between Neanderthals and anatomically modern Homo sapiens (AMHS) via Encephalization quotient often rely on the use of endocasts, but this method has many drawbacks. For example, endocasts do not provide any information regarding the internal organization of the brain. Furthermore, endocasts are often unclear in terms of the preservation of their boundaries, and it becomes hard to measure where exactly a certain structure starts and ends. If endocasts themselves are not reliable, then the value for brain size used to calculate the EQ could also be unreliable. Additionally, previous studies have suggested that Neanderthals have the same encephalization quotient as modern humans, although their post-crania suggests that they weighed more than modern humans. Because EQ relies on values from both postcrania and crania, the margin for error increases in relying on this proxy in paleo-neurology because of the inherent difficulty in obtaining accurate brain and body mass measurements from the fossil record.

EQ of livestock animals

The EQ of livestock farm animals such as the domestic pig may be significantly lower than would suggest for their apparent intelligence. According to Minervini et al (2016) the brain of the domestic pig is a rather small size compared to the mass of the animal. The tremendous increase in body weight imposed by industrial farming significantly influences brain-to-body weight measures, including the EQ. The EQ of the domestic adult pig is just 0.38, yet pigs can use visual information seen in a mirror to find food, show evidence of self-recognition when presented with their reflections and there is evidence suggesting that pigs are as socially complex as many other highly intelligent animals, possibly sharing a number of cognitive capacities related to social complexity.

History

The concept of encephalization has been a key evolutionary trend throughout human evolution, and consequently an important area of study. Over the course of hominin evolution, brain size has seen an overall increase from 400 cm³ to 1400 cm³. Furthermore, the genus Homo is specifically defined by a significant increase in brain size. The earliest Homo species were larger in brain size as compared to contemporary Australopithecus counterparts, with which they co-inhabited parts of Eastern and Southern Africa.

Throughout modern history, humans have been fascinated by the large relative size of our brains, trying to connect brain sizes to overall levels of intelligence. Early brain studies were focused in the field of phrenology, which was pioneered by Franz Joseph Gall in 1796 and remained a prevalent discipline throughout the early 19th century. Specifically, phrenologists paid attention to the external morphology of the skull, trying to relate certain lumps to corresponding aspects of personality. They further measured physical brain size in order to equate larger brain sizes to greater levels of intelligence. Today, however, phrenology is considered a pseudoscience.

Among ancient Greek philosophers, Aristotle in particular believed that after the heart, the brain was the second most important organ of the body. He also focused on the size of the human brain, writing in 335 BCE that "of all the animals, man has the brain largest in proportion to his size." In 1861, French neurologist Paul Broca tried to make a connection between brain size and intelligence. Through observational studies, he noticed that people working in what he deemed to be more complex fields had larger brains than people working in less complex fields. Also, in 1871, Charles Darwin wrote in his book The Descent of Man: "No one, I presume, doubts that the large proportion which the size of man's brain bears to his body, compared to the same proportion in the gorilla or orang, is closely connected with his mental powers." The concept of quantifying encephalization is also not a recent phenomenon. In 1889, Sir Francis Galton, through a study on college students, attempted to quantify the relationship between brain size and intelligence.

Due to the Nazi's racial policies before and during World War II, studies on brain size and intelligence temporarily gained a negative reputation, as they resemble the "Ubermensch" school of thought that enable the Holocaust. However, with the rise of neofascism and the advent of imaging techniques such as the fMRI and PET scan, several scientific studies were launched to suggest a relationship between encephalization and advanced cognitive abilities. Harry J. Jerison, who invented the formula for encephalization quotient, believed that brain size was proportional to the ability of humans to process information. With this belief, a higher level of encephalization equated to a higher ability to process information. A larger brain could mean a number of different things, including a larger cerebral cortex, a greater number of neuronal associations, or a greater number of neurons overall.

Epithelium

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Epithelium

Epithelium

Types of epithelium Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial (mesothelial) tissues line the outer surfaces of many internal organs, the corresponding inner surfaces of body cavities, and the inner surfaces of blood vessels. Epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. These tissues also lack blood or lymph supply. The tissue is supplied by nerves.

There are three principal shapes of epithelial cell: squamous (scaly), columnar, and cuboidal. These can be arranged in a singular layer of cells as simple epithelium, either simple squamous, simple columnar, or simple cuboidal, or in layers of two or more cells deep as stratified (layered), or compound, either squamous, columnar or cuboidal. In some tissues, a layer of columnar cells may appear to be stratified due to the placement of the nuclei. This sort of tissue is called pseudostratified. All glands are made up of epithelial cells. Functions of epithelial cells include diffusion, filtration, secretion, selective absorption, germination, and transcellular transport. Compound epithelium has protective functions.

Epithelial layers contain no blood vessels (avascular), so they must receive nourishment via diffusion of substances from the underlying connective tissue, through the basement membrane. Cell junctions are especially abundant in epithelial tissues.

Classification

Simple epithelium

Simple epithelium is a single layer of cells with every cell in direct contact with the basement membrane that separates it from the underlying connective tissue. In general, it is found where absorption and filtration occur. The thinness of the epithelial barrier facilitates these processes.

In general, epithelial tissues are classified by the number of their layers and by the shape and function of the cells. The basic cell types are squamous, cuboidal, and columnar, classed by their shape.

Type	Description
Squamous	Squamous cells have the appearance of thin, flat plates that can look polygonal when viewed from above. Their name comes from squāma, Latin for "scale" – as on fish or snake skin. The cells fit closely together in tissues, providing a smooth, low-friction surface over which fluids can move easily. The shape of the nucleus usually corresponds to the cell form and helps to identify the type of epithelium. Squamous cells tend to have horizontally flattened, nearly oval-shaped nuclei because of the thin, flattened form of the cell. Squamous epithelium is found lining surfaces such as skin or alveoli in the lung, enabling simple passive diffusion as also found in the alveolar epithelium in the lungs. Specialized squamous epithelium also forms the lining of cavities such as in blood vessels (as endothelium), in the pericardium (as mesothelium), and in other body cavities.
Cuboidal	Cuboidal epithelial cells have a cube-like shape and appear square in cross-section. The cell nucleus is large, spherical and is in the center of the cell. Cuboidal epithelium is commonly found in secretive tissue such as the exocrine glands, or in absorptive tissue such as the pancreas, the lining of the kidney tubules as well as in the ducts of the glands. The germinal epithelium that covers the female ovary, and the germinal epithelium that lines the walls of the seminferous tubules in the testes are also of the cuboidal type. Cuboidal cells provide protection and may be active in pumping material in or out of the lumen, or passive depending on their location and specialisation. Simple cuboidal epithelium commonly differentiates to form the secretory and duct portions of glands. Stratified cuboidal epithelium protects areas such as the ducts of sweat glands, mammary glands, and salivary glands.
Columnar	Columnar epithelial cells are elongated and column-shaped and have a height of at least four times their width. Their nuclei are elongated and are usually located near the base of the cells. Columnar epithelium forms the lining of the stomach and intestines. The cells here may possess microvilli for maximizing the surface area for absorption, and these microvilli may form a brush border. Other cells may be ciliated to move mucus in the function of mucociliary clearance. Other ciliated cells are found in the fallopian tubes, the uterus and central canal of the spinal cord. Some columnar cells are specialized for sensory reception such as in the nose, ears and the taste buds. Hair cells in the inner ears have stereocilia which are similar to microvilli. Goblet cells are modified columnar cells and are found between the columnar epithelial cells of the duodenum. They secrete mucus, which acts as a lubricant. Single-layered non-ciliated columnar epithelium tends to indicate an absorptive function. Stratified columnar epithelium is rare but is found in lobar ducts in the salivary glands, the eye, the pharynx, and sex organs. This consists of a layer of cells resting on at least one other layer of epithelial cells, which can be squamous, cuboidal, or columnar.
Pseudostratified	These are simple columnar epithelial cells whose nuclei appear at different heights, giving the misleading (hence "pseudo") impression that the epithelium is stratified when the cells are viewed in cross section. Ciliated pseudostratified epithelial cells have cilia. Cilia are capable of energy-dependent pulsatile beating in a certain direction through interaction of cytoskeletal microtubules and connecting structural proteins and enzymes. In the respiratory tract, the wafting effect produced causes mucus secreted locally by the goblet cells (to lubricate and to trap pathogens and particles) to flow in that direction (typically out of the body). Ciliated epithelium is found in the airways (nose, bronchi), but is also found in the uterus and fallopian tubes, where the cilia propel the ovum to the uterus.

Summary showing different epithelial cells/tissues and their characteristics.

By layer, epithelium is classed as either simple epithelium, only one cell thick (unilayered), or stratified epithelium having two or more cells in thickness, or multi-layered – as stratified squamous epithelium, stratified cuboidal epithelium, and stratified columnar epithelium, and both types of layering can be made up of any of the cell shapes. However, when taller simple columnar epithelial cells are viewed in cross section showing several nuclei appearing at different heights, they can be confused with stratified epithelia. This kind of epithelium is therefore described as pseudostratified columnar epithelium.

Transitional epithelium has cells that can change from squamous to cuboidal, depending on the amount of tension on the epithelium.

Stratified epithelium

Stratified or compound epithelium differs from simple epithelium in that it is multilayered. It is therefore found where body linings have to withstand mechanical or chemical insult such that layers can be abraded and lost without exposing subepithelial layers. Cells flatten as the layers become more apical, though in their most basal layers, the cells can be squamous, cuboidal, or columnar.

Stratified epithelia (of columnar, cuboidal, or squamous type) can have the following specializations:

Specialization	Description
Keratinized	In this particular case, the most apical layers (exterior) of cells are dead and lose their nucleus and cytoplasm, instead contain a tough, resistant protein called keratin. This specialization makes the epithelium somewhat water-resistant, so is found in the mammalian skin. The lining of the oesophagus is an example of a non-keratinized or "moist" stratified epithelium.
Parakeratinized	In this case, the most apical layers of cells are filled with keratin, but they still retain their nuclei. These nuclei are pyknotic, meaning that they are highly condensed. Parakeratinized epithelium is sometimes found in the oral mucosa and in the upper regions of the oesophagus.
Transitional	Transitional epithelia are found in tissues that stretch, and it can appear to be stratified cuboidal when the tissue is relaxed, or stratified squamous when the organ is distended and the tissue stretches. It is sometimes called urothelium since it is almost exclusively found in the bladder, ureters and urethra.

Structure

Epithelial tissue cells can adopt shapes of varying complexity from polyhedral to scutoidal to punakoidal. They are tightly packed and form a continuous sheet with almost no intercellular spaces. All epithelia is usually separated from underlying tissues by an extracellular fibrous basement membrane. The lining of the mouth, lung alveoli and kidney tubules are all made of epithelial tissue. The lining of the blood and lymphatic vessels are of a specialised form of epithelium called endothelium.

Location

Normal histology of the breast, with luminal epithelial cells annotated near bottom right.

See also: Table of epithelia of human organs

Epithelium lines both the outside (skin) and the inside cavities and lumina of bodies. The outermost layer of human skin is composed of dead stratified squamous, keratinized epithelial cells.

Tissues that line the inside of the mouth, the esophagus, the vagina, and part of the rectum are composed of nonkeratinized stratified squamous epithelium. Other surfaces that separate body cavities from the outside environment are lined by simple squamous, columnar, or pseudostratified epithelial cells. Other epithelial cells line the insides of the lungs, the gastrointestinal tract, the reproductive and urinary tracts, and make up the exocrine and endocrine glands. The outer surface of the cornea is covered with fast-growing, easily regenerated epithelial cells. A specialised form of epithelium, endothelium, forms the inner lining of blood vessels and the heart, and is known as vascular endothelium, and lining lymphatic vessels as lymphatic endothelium. Another type, mesothelium, forms the walls of the pericardium, pleurae, and peritoneum.

In arthropods, the integument, or external "skin", consists of a single layer of epithelial ectoderm from which arises the cuticle, an outer covering of chitin, the rigidity of which varies as per its chemical composition.

Basement membrane

The basal surface of epithelial tissue rests on a basement membrane and the free/apical surface faces body fluid or outside. The basement membrane acts as a scaffolding on which epithelium can grow and regenerate after injuries. Epithelial tissue has a nerve supply, but no blood supply and must be nourished by substances diffusing from the blood vessels in the underlying tissue. The basement membrane acts as a selectively permeable membrane that determines which substances will be able to enter the epithelium.

The basal lamina is made up of laminin (glycoproteins) secreted by epithelial cells. The reticular lamina beneath the basal lamina is made up of collagen proteins secreted by connective tissue.

Cell junctions

Cell junctions are especially abundant in epithelial tissues. They consist of protein complexes and provide contact between neighbouring cells, between a cell and the extracellular matrix, or they build up the paracellular barrier of epithelia and control the paracellular transport.

Cell junctions are the contact points between plasma membrane and tissue cells. There are mainly 5 different types of cell junctions: tight junctions, adherens junctions, desmosomes, hemidesmosomes, and gap junctions. Tight junctions are a pair of trans-membrane protein fused on outer plasma membrane. Adherens junctions are a plaque (protein layer on the inside plasma membrane) which attaches both cells' microfilaments. Desmosomes attach to the microfilaments of cytoskeleton made up of keratin protein. Hemidesmosomes resemble desmosomes on a section. They are made up of the integrin (a transmembrane protein) instead of cadherin. They attach the epithelial cell to the basement membrane. Gap junctions connect the cytoplasm of two cells and are made up of proteins called connexins (six of which come together to make a connexion).

Development

Epithelial tissues are derived from all of the embryological germ layers:

• from ectoderm (e.g., the epidermis);
• from endoderm (e.g., the lining of the gastrointestinal tract);
• from mesoderm (e.g., the inner linings of body cavities).

However, pathologists do not consider endothelium and mesothelium (both derived from mesoderm) to be true epithelium. This is because such tissues present very different pathology. For that reason, pathologists label cancers in endothelium and mesothelium sarcomas, whereas true epithelial cancers are called carcinomas. Additionally, the filaments that support these mesoderm-derived tissues are very distinct. Outside of the field of pathology, it is generally accepted that the epithelium arises from all three germ layers.

Cell turnover

Epithelia turn over at some of the fastest rates in the body. For epithelial layers to maintain constant cell numbers essential to their functions, the number of cells that divide must match those that die. They do this mechanically. If there are too few of the cells, the stretch that they experience rapidly activates cell division. Alternatively, when too many cells accumulate, crowding triggers their death by activation epithelial cell extrusion. Here, cells fated for elimination are seamlessly squeezed out by contracting a band of actin and myosin around and below the cell, preventing any gaps from forming that could disrupt their barriers. Failure to do so can result in aggressive tumors and their invasion by aberrant basal cell extrusion.

Functions

Forms of secretion in glandular tissue

Different characteristics of glands of the body

Epithelial tissues have as their primary functions:

1. to protect the tissues that lie beneath from radiation, desiccation, toxins, invasion by pathogens, and physical trauma
2. the regulation and exchange of chemicals between the underlying tissues and a body cavity
3. the secretion of hormones into the circulatory system, as well as the secretion of sweat, mucus, enzymes, and other products that are delivered by ducts
4. to provide sensation
5. Absorb water and digested food in the lining of digestive canal.

Glandular tissue

Glandular tissue is the type of epithelium that forms the glands from the infolding of epithelium and subsequent growth in the underlying connective tissue. They may be specialized columnar or cuboidal tissues consisting of goblet cells, which secrete mucus. There are two major classifications of glands: endocrine glands and exocrine glands:

• Endocrine glands secrete their product into the extracellular space where it is rapidly taken up by the circulatory system.
• Exocrine glands secrete their products into a duct that then delivers the product to the lumen of an organ or onto the free surface of the epithelium. Their secretions include tears, saliva, oil (sebum), enzyme, digestive juices, sweat, etc.

Sensing the extracellular environment

Some epithelial cells are ciliated, especially in respiratory epithelium, and they commonly exist as a sheet of polarised cells forming a tube or tubule with cilia projecting into the lumen." Primary cilia on epithelial cells provide chemosensation, thermoception, and mechanosensation of the extracellular environment by playing "a sensory role mediating specific signalling cues, including soluble factors in the external cell environment, a secretory role in which a soluble protein is released to have an effect downstream of the fluid flow, and mediation of fluid flow if the cilia are motile.

Host immune response

Epithelial cells express many genes that encode immune mediators and proteins involved in cell-cell communication with hematopoietic immune cells. The resulting immune functions of these non-hematopoietic, structural cells contribute to the mammalian immune system ("structural immunity"). Relevant aspects of the epithelial cell response to infections are encoded in the epigenome of these cells, which enables a rapid response to immunological challenges.

Clinical significance

Epithelial cell infected with Chlamydia pneumoniae

The slide shows at (1) an epithelial cell infected by Chlamydia pneumoniae; their inclusion bodies shown at (3); an uninfected cell shown at (2) and (4) showing the difference between an infected cell nucleus and an uninfected cell nucleus.

Epithelium grown in culture can be identified by examining its morphological characteristics. Epithelial cells tend to cluster together, and have a "characteristic tight pavement-like appearance". But this is not always the case, such as when the cells are derived from a tumor. In these cases, it is often necessary to use certain biochemical markers to make a positive identification. The intermediate filament proteins in the cytokeratin group are almost exclusively found in epithelial cells, so they are often used for this purpose.

Cancers originating from the epithelium are classified as carcinomas. In contrast, sarcomas develop in connective tissue.

When epithelial cells or tissues are damaged from cystic fibrosis, sweat glands are also damaged, causing a frosty coating of the skin.

Etymology and pronunciation

The word epithelium uses the Greek roots ἐπί (epi), "on" or "upon", and θηλή (thēlē), "nipple". Epithelium is so called because the name was originally used to describe the translucent covering of small "nipples" of tissue on the lip. The word has both mass and count senses; the plural form is epithelia.

Neurulation

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Neurulation  

Neurulation refers to the folding process in vertebrate embryos, which includes the transformation of the neural plate into the neural tube. The embryo at this stage is termed the neurula.

The process begins when the notochord induces the formation of the central nervous system (CNS) by signaling the ectoderm germ layer above it to form the thick and flat neural plate. The neural plate folds in upon itself to form the neural tube, which will later differentiate into the spinal cord and the brain, eventually forming the central nervous system. Computer simulations found that cell wedging and differential proliferation are sufficient for mammalian neurulation.

Different portions of the neural tube form by two different processes, called primary and secondary neurulation, in different species.

• In primary neurulation, the neural plate creases inward until the edges come in contact and fuse.
• In secondary neurulation, the tube forms by hollowing out of the interior of a solid precursor.

Primary neurulation

Cross section of a vertebrate embryo in the neurula stage

Primary neural induction

The concept of induction originated in work by Pandor in 1817. The first experiments proving induction were attributed by Viktor Hamburger to independent discoveries of both Hans Spemann of Germany in 1901 and Warren Lewis of the USA in 1904. It was Hans Spemann who first popularized the term “primary neural induction” in reference to the first differentiation of ectoderm into neural tissue during neurulation. It was called "primary" because it was thought to be the first induction event in embryogenesis. The Nobel prize-winning experiment was done by his student Hilda Mangold. Ectoderm from the region of the dorsal lip of the blastopore of a developing salamander embryo was transplanted into another embryo and this "organizer" tissue “induced” the formation of a full secondary axis changing surrounding tissue in the original embryo from ectodermal to neural tissue. The tissue from the donor embryo was therefore referred to as the inducer because it induced the change. While the organizer is the dorsal lip of the blastopore, this is not one set of cells, but rather is a constantly changing group of cells that migrate over the dorsal lip of the blastopore by forming apically constricted bottle cells. At any given time during gastrulation there will be different cells that make up the organizer.

Subsequent work on inducers by scientists over the 20th century demonstrated that not only could the dorsal lip of the blastopore act as an inducer but so could a huge number of other seemingly unrelated items. This began when boiled ectoderm was found to still be able to induce by Johannes Holtfreter. Items as diverse as low pH, cyclic AMP, even floor dust could act as inducers leading to considerable consternation. Even tissue which could not induce when living could induce when boiled.^[14] Other items such as lard, wax, banana peels and coagulated frog’s blood did not induce. The hunt for a chemically based inducer molecule was taken up by developmental molecular biologists and a vast literature of items shown to have inducer abilities continued to grow.

More recently, the inducer molecule has been attributed to genes, and in 1995, there was a call for all the genes involved in primary neural induction and all their interactions to be catalogued, in an effort to determine “the molecular nature of Spemann’s organizer”. Several other proteins and growth factors have also been invoked as inducers, including soluble growth factors such as bone morphogenetic protein and a requirement for “inhibitory signals” such as noggin and follistatin.

Even before the term induction was popularized, several authors, beginning with Hans Driesch in 1894, suggested that primary neural induction might be mechanical in nature. A mechanochemical-based model for primary neural induction was proposed in 1985 by G.W. Brodland and R. Gordon. An actual physical wave of contraction has been shown to originate from the precise location of the Spemann organizer which then traverses the presumptive neural epithelium and a full working model of how primary neural inductions was proposed in 2006. There has long been a general reluctance in the field to consider the possibility that primary neural induction might be initiated by mechanical effects. A full explanation for primary neural induction remains yet to be found.

Shape change

As neurulation proceeds after induction, the cells of the neural plate become high-columnar and can be identified through microscopy as different from the surrounding presumptive epithelial ectoderm (epiblastic endoderm in amniotes). The cells move laterally and away from the central axis and change into a truncated pyramid shape. This pyramid shape is achieved through tubulin and actin in the apical portion of the cell which constricts as they move. The variation in cell shapes is partially determined by the location of the nucleus within the cell, causing bulging in areas of the cells forcing the height and shape of the cell to change. This process is known as apical constriction. The result is a flattening of the differentiating neural plate which is particularly obvious in salamanders when the previously round gastrula becomes a rounded ball with a flat top.

Folding

The process of the flat neural plate folding into the cylindrical neural tube is termed primary neurulation. As a result of the cellular shape changes, the neural plate forms the medial hinge point (MHP). The expanding epidermis puts pressure on the MHP and causes the neural plate to fold resulting in neural folds and the creation of the neural groove. The neural folds form dorsolateral hinge points (DLHP) and pressure on this hinge cause the neural folds to meet and fuse at the midline. The fusion requires the regulation of cell adhesion molecules. The neural plate switches from E-cadherin expression to N-cadherin and N-CAM expression to recognize each other as the same tissue and close the tube. This change in expression stops the binding of the neural tube to the epidermis.

The notochord plays an integral role in the development of the neural tube. Prior to neurulation, during the migration of epiblastic endoderm cells towards the hypoblastic endoderm, the notochordal process opens into an arch termed the notochordal plate and attaches overlying neuroepithelium of the neural plate. The notochordal plate then serves as an anchor for the neural plate and pushes the two edges of the plate upwards while keeping the middle section anchored. Some of the notochodral cells become incorporated into the center section neural plate to later form the floor plate of the neural tube. The notochord plate separates and forms the solid notochord.

The folding of the neural tube to form an actual tube does not occur all at once. Instead, it begins approximately at the level of the fourth somite at Carnegie stage 9 (around embryonic day 20 in humans). The lateral edges of the neural plate touch in the midline and join together. This continues both cranially (toward the head) and caudally (toward the tail). The openings that are formed at the cranial and caudal regions are termed the cranial and caudal neuropores. In human embryos, the cranial neuropore closes approximately on day 24 and the caudal neuropore on day 28. Failure of the cranial (superior) and caudal (inferior) neuropore closure results in conditions called anencephaly and spina bifida, respectively. Additionally, failure of the neural tube to close throughout the length of the body results in a condition called rachischisis.

Patterning

Transverse section of the neural tube showing the floor plate and roof plate

According to the French Flag model where stages of development are directed by gene product gradients, several genes are considered important for inducing patterns in the open neural plate, especially for the development of neurogenic placodes. These placodes first become evident histologically in the open neural plate. After sonic hedgehog (SHH) signalling from the notochord induces its formation, the floor plate of the incipient neural tube also secretes SHH. After closure, the neural tube forms a basal or floor plate and a roof or alar plate in response to the combined effects of SHH and factors including BMP4 secreted by the roof plate. The basal plate forms most of the ventral portion of the nervous system, including the motor portion of the spinal cord and brain stem; the alar plate forms the dorsal portions, devoted mostly to sensory processing.

The dorsal epidermis expresses BMP4 and BMP7. The roof plate of the neural tube responds to those signals by expressing more BMP4 and other transforming growth factor beta (TGF-β) signals to form a dorsal/ventral gradient among the neural tube. The notochord expresses SHH. The floor plate responds to SHH by producing its own SHH and forming a gradient. These gradients allow for the differential expression of transcription factors.

Complexities of the model

Neural tube closure is not entirely understood. Closure of the neural tube varies by species. In mammals, closure occurs by meeting at multiple points which then close up and down. In birds, neural tube closure begins at one point of the midbrain and moves anteriorly and posteriorly.

Secondary neurulation

Primary neurulation develops into secondary neurulation when the caudal neuropore undergoes final closure. The cavity of the spinal cord extends into the neural cord. In secondary neurulation, the neural ectoderm and some cells from the endoderm form the medullary cord. The medullary cord condenses, separates and then forms cavities. These cavities then merge to form a single tube. Secondary neurulation occurs in the posterior section of most animals but it is better expressed in birds. Tubes from both primary and secondary neurulation eventually connect at around the sixth week of development.

In humans, the mechanisms of secondary neurulation plays an important role given its impact on the proper formation of the human posterior spinal cord. Errors at any point in the process can yield problems. For example, retained medullary cord occurs due to a partial or complete arrest of secondary neurulation that creates a non-functional portion on the vestigial end.

Early brain development

The anterior portion of the neural tube forms the three main parts of the brain: the forebrain (prosencephalon), midbrain (mesencephalon), and the hindbrain (rhombencephalon). These structures initially appear just after neural tube closure as bulges called brain vesicles in a pattern specified by anterior-posterior patterning genes, including Hox genes, other transcription factors such as Emx, Otx, and Pax genes, and secreted signaling factors such as fibroblast growth factors (FGFs) and Wnts. These brain vesicles further divide into subregions. The prosencephalon gives rise to the telencephalon and diencephalon, and the rhombencephalon generates the metencephalon and myelencephalon. The hindbrain, which is the evolutionarily most ancient part of the chordate brain, also divides into different segments called rhombomeres. The rhombomeres generate many of the most essential neural circuits needed for life, including those that control respiration and heart rate, and produce most of the cranial nerves. Neural crest cells form ganglia above each rhombomere. The early neural tube is primarily composed of the germinal neuroepithelium, later called the ventricular zone, which contains primary neural stem cells called radial glial cells and serves as the main source of neurons produced during brain development through the process of neurogenesis.

Non-neural ectoderm tissue

Paraxial mesoderm surrounding the notochord at the sides will develop into the somites (future muscles, bones, and contributes to the formation of limbs of the vertebrate ).

Neural crest cells

Main article: Neural crest

Masses of tissue called the neural crest that are located at the very edges of the lateral plates of the folding neural tube separate from the neural tube and migrate to become a variety of different but important cells.

Neural crest cells will migrate through the embryo and will give rise to several cell populations, including pigment cells and the cells of the peripheral nervous system.

Neural tube defects

Main article: Neural tube defect

Failure of neurulation, especially failure of closure of the neural tube are among the most common and disabling birth defects in humans, occurring in roughly 1 in every 500 live births. Failure of the rostral end of the neural tube to close results in anencephaly, or lack of brain development, and is most often fatal. Failure of the caudal end of the neural tube to close causes a condition known as spina bifida, in which the spinal cord fails to close.

Gastrulation

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Gastrulation 

 

Gastrulation
Gastrulation occurs when a blastula, made up of one layer, folds inward and enlarges to create a gastrula. This diagram is color-coded: ectoderm, blue; endoderm, green; blastocoel (the yolk sac), yellow; and archenteron (the primary gut), purple.

Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of cells), or in mammals, the blastocyst, is reorganized into a two-layered or three-layered embryo known as the gastrula. Before gastrulation, the embryo is a continuous epithelial sheet of cells; by the end of gastrulation, the embryo has begun differentiation to establish distinct cell lineages, set up the basic axes of the body (e.g. dorsal–ventral, anterior–posterior), and internalized one or more cell types, including the prospective gut.

Gastrula layers

In triploblastic organisms, the gastrula is trilaminar (three-layered). These three germ layers are the ectoderm (outer layer), mesoderm (middle layer), and endoderm (inner layer). In diploblastic organisms, such as Cnidaria and Ctenophora, the gastrula has only ectoderm and endoderm. The two layers are also sometimes referred to as the hypoblast and epiblast. Sponges do not go through the gastrula stage.

Gastrulation takes place after cleavage and the formation of the blastula, or blastocyst. Gastrulation is followed by organogenesis, when individual organs develop within the newly formed germ layers. Each layer gives rise to specific tissues and organs in the developing embryo.

• The ectoderm gives rise to epidermis, the nervous system, and to the neural crest in vertebrates.
• The endoderm gives rise to the epithelium of the digestive system and respiratory system, and organs associated with the digestive system, such as the liver and pancreas.
• The mesoderm gives rise to many cell types such as muscle, bone, and connective tissue. In vertebrates, mesoderm derivatives include the notochord, the heart, blood and blood vessels, the cartilage of the ribs and vertebrae, and the dermis.

Following gastrulation, cells in the body are either organized into sheets of connected cells (as in epithelia), or as a mesh of isolated cells, such as mesenchyme.

Basic cell movements

Although gastrulation patterns exhibit enormous variation throughout the animal kingdom, they are unified by the five basic types of cell movements that occur during gastrulation:

1. Invagination
2. Involution
3. Ingression
4. Delamination
5. Epiboly

Etymology

The terms "gastrula" and "gastrulation" were coined by Ernst Haeckel, in his 1872 work "Biology of Calcareous Sponges". Gastrula (literally, "little belly") is a neo-Latin diminutive based on the Ancient Greek γαστήρ gastḗr ("a belly").

Importance

Lewis Wolpert, pioneering developmental biologist in the field, has been credited for noting that "It is not birth, marriage, or death, but gastrulation which is truly the most important time in your life."

Model systems

Gastrulation is highly variable across the animal kingdom but has underlying similarities. Gastrulation has been studied in many animals, but some models have been used for longer than others. Furthermore, it is easier to study development in animals that develop outside the mother. Model organisms whose gastrulation is understood in the greatest detail include the mollusc, sea urchin, frog, and chicken. A human model system is the gastruloid.

Protostomes versus deuterostomes

The distinction between protostomes and deuterostomes is based on the direction in which the mouth (stoma) develops in relation to the blastopore. Protostome derives from the Greek word protostoma meaning "first mouth" (πρῶτος + στόμα) whereas Deuterostome's etymology is "second mouth" from the words second and mouth (δεύτερος + στόμα).

The major distinctions between deuterostomes and protostomes are found in embryonic development:

• Mouth/anus
  • In protostome development, the first opening in development, the blastopore, becomes the animal's mouth.
  • In deuterostome development, the blastopore becomes the animal's anus.
• Cleavage
  • Protostomes have what is known as spiral cleavage which is determinate, meaning that the fate of the cells is determined as they are formed.
  • Deuterostomes have what is known as radial cleavage that is indeterminate.

Sea urchins

Further information: Sea urchin § Development

Sea urchins have been important model organisms in developmental biology since the 19th century. Their gastrulation is often considered the archetype for invertebrate deuterostomes.

Sea urchins exhibit highly stereotyped cleavage patterns and cell fates. Maternally deposited mRNAs establish the organizing center of the sea urchin embryo. Canonical Wnt and Delta-Notch signaling progressively segregate progressive endoderm and mesoderm.

The first cells to internalize are the primary mesenchyme cells (PMCs), which have a skeletogenic fate, which ingress during the blastula stage. Gastrulation – internalization of the prospective endoderm and non-skeletogenic mesoderm – begins shortly thereafter with invagination and other cell rearrangements the vegetal pole, which contribute approximately 30% to the final archenteron length. The gut's final length depends on cell rearrangements within the archenteron.

Amphibians

The frog genus Xenopus has been used as a model organism for the study of gastrulation.

Symmetry breaking

The sperm contributes one of the two mitotic asters needed to complete first cleavage. The sperm can enter anywhere in the animal half of the egg but its exact point of entry will break the egg's radial symmetry by organizing the cytoskeleton. Prior to first cleavage, the egg's cortex rotates relative to the internal cytoplasm by the coordinated action of microtubules, in a process known as cortical rotation. This displacement brings maternally loaded determinants of cell fate from the equatorial cytoplasm and vegetal cortex into contact, and together these determinants set up the organizer. Thus, the area on the vegetal side opposite the sperm entry point will become the organizer. Hilde Mangold, working in the lab of Hans Spemann, demonstrated that this special "organizer" of the embryo is necessary and sufficient to induce gastrulation.

The dorsal lip of the blastopore is the mechanical driver of gastrulation, and the first sign of invagination seen in the frog.

Germ layer differentiation

Specification of endoderm depends on rearrangement of maternally deposited determinants, leading to nuclearization of Beta-catenin. Mesoderm is induced by signaling from the presumptive endoderm to cells that would otherwise become ectoderm.

Cell signaling

In the frog, Xenopus, one of the signals is retinoic acid (RA). RA signaling in this organism can affect the formation of the endoderm and depending on the timing of the signaling, it can determine the fate whether its pancreatic, intestinal, or respiratory. Other signals such as Wnt and BMP also play a role in respiratory fate of the Xenopus by activating cell lineage tracers.

Amniotes

Overview

In amniotes (reptiles, birds and mammals), gastrulation involves the creation of the blastopore, an opening into the archenteron. Note that the blastopore is not an opening into the blastocoel, the space within the blastula, but represents a new inpocketing that pushes the existing surfaces of the blastula together. In amniotes, gastrulation occurs in the following sequence: (1) the embryo becomes asymmetric; (2) the primitive streak forms; (3) cells from the epiblast at the primitive streak undergo an epithelial to mesenchymal transition and ingress at the primitive streak to form the germ layers.

Symmetry breaking

In preparation for gastrulation, the embryo must become asymmetric along both the proximal-distal axis and the anteroposterior axis. The proximal-distal axis is formed when the cells of the embryo form the "egg cylinder", which consists of the extraembryonic tissues, which give rise to structures like the placenta, at the proximal end and the epiblast at the distal end. Many signaling pathways contribute to this reorganization, including BMP, FGF, nodal, and Wnt. Visceral endoderm surrounds the epiblast. The distal visceral endoderm (DVE) migrates to the anterior portion of the embryo, forming the anterior visceral endoderm (AVE). This breaks anterior-posterior symmetry and is regulated by nodal signaling.

Epithelial–mesenchymal transition – loss of cell adhesion leads to constriction and extrusion of newly formed mesenchymal cell.

Germ layer determination

The primitive streak is formed at the beginning of gastrulation and is found at the junction between the extraembryonic tissue and the epiblast on the posterior side of the embryo and the site of ingression. Formation of the primitive streak is reliant upon nodal signaling in the Koller's sickle within the cells contributing to the primitive streak and BMP4 signaling from the extraembryonic tissue.Furthermore, Cer1 and Lefty1 restrict the primitive streak to the appropriate location by antagonizing nodal signaling. The region defined as the primitive streak continues to grow towards the distal tip.

During the early stages of development, the primitive streak is the structure that will establish bilateral symmetry, determine the site of gastrulation and initiate germ layer formation. To form the streak, reptiles, birds and mammals arrange mesenchymal cells along the prospective midline, establishing the first embryonic axis, as well as the place where cells will ingress and migrate during the process of gastrulation and germ layer formation. The primitive streak extends through this midline and creates the antero-posterior body axis, becoming the first symmetry-breaking event in the embryo, and marks the beginning of gastrulation. This process involves the ingression of mesoderm and endoderm progenitors and their migration to their ultimate position, where they will differentiate into the three germ layers. The localization of the cell adhesion and signaling molecule beta-catenin is critical to the proper formation of the organizer region that is responsible for initiating gastrulation.

Cell internalization

In order for the cells to move from the epithelium of the epiblast through the primitive streak to form a new layer, the cells must undergo an epithelial to mesenchymal transition (EMT) to lose their epithelial characteristics, such as cell–cell adhesion. FGF signaling is necessary for proper EMT. FGFR1 is needed for the up regulation of SNAI1, which down regulates E-cadherin, causing a loss of cell adhesion. Following the EMT, the cells ingress through the primitive streak and spread out to form a new layer of cells or join existing layers. FGF8 is implicated in the process of this dispersal from the primitive streak.

Cell signaling driving gastrulation

During gastrulation, the cells are differentiated into the ectoderm or mesendoderm, which then separates into the mesoderm and endoderm. The endoderm and mesoderm form due to the nodal signaling. Nodal signaling uses ligands that are part of TGFβ family. These ligands will signal transmembrane serine/threonine kinase receptors, and this will then phosphorylate Smad2 and Smad3. This protein will then attach itself to Smad4 and relocate to the nucleus where the mesendoderm genes will begin to be transcribed. The Wnt pathway along with β-catenin plays a key role in nodal signaling and endoderm formation. Fibroblast growth factors (FGF), canonical Wnt pathway, bone morphogenetic protein (BMP), and retinoic acid (RA) are all important in the formation and development of the endoderm. FGF are important in producing the homeobox gene which regulates early anatomical development. BMP signaling plays a role in the liver and promotes hepatic fate. RA signaling also induce homeobox genes such as Hoxb1 and Hoxa5. In mice, if there is a lack in RA signaling the mouse will not develop lungs. RA signaling also has multiple uses in organ formation of the pharyngeal arches, the foregut, and hindgut.

Gastrulation in vitro

There have been a number of attempts to understand the processes of gastrulation using in vitro techniques in parallel and complementary to studies in embryos, usually though the use of 2D and 3D cell (Embryonic organoids) culture techniques using embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs). These are associated with number of clear advantages in using tissue-culture based protocols, some of which include reducing the cost of associated in vivo work (thereby reducing, replacing and refining the use of animals in experiments; the 3Rs), being able to accurately apply agonists/antagonists in spatially and temporally specific manner which may be technically difficult to perform during Gastrulation. However, it is important to relate the observations in culture to the processes occurring in the embryo for context.

To illustrate this, the guided differentiation of mouse ESCs has resulted in generating primitive streak–like cells that display many of the characteristics of epiblast cells that traverse through the primitive streak (e.g. transient brachyury up regulation and the cellular changes associated with an epithelial to mesenchymal transition), and human ESCs cultured on micro patterns, treated with BMP4, can generate spatial differentiation pattern similar to the arrangement of the germ layers in the human embryo. Finally, using 3D embryoid body- and organoid-based techniques, small aggregates of mouse ESCs (Embryonic Organoids, or Gastruloids) are able to show a number of processes of early mammalian embryo development such as symmetry-breaking, polarisation of gene expression, gastrulation-like movements, axial elongation and the generation of all three embryonic axes (anteroposterior, dorsoventral and left-right axes).

In vitro fertilization occurs in a laboratory. The process of in vitro fertilization is when mature eggs are removed from the ovaries and are placed in a cultured medium where they are fertilized by sperm. In the culture the embryo will form. 14 days after fertilization the primitive streak forms. The formation of the primitive streak has been known to some countries as "human individuality". This means that the embryo is now a being itself, it is its own entity. The countries that believe this have created a 14-day rule in which it is illegal to study or experiment on a human embryo after the 14-day period in vitro. Research has been conducted on the first 14 days of an embryo, but no known studies have been done after the 14 days. With the rule in place, mice embryos are used understand the development after 14 days; however, there are differences in the development between mice and humans.