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Do primitive streak cells remain with us?

Do primitive streak cells remain with us?


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Is there any evidence or experiments to show, that cells from the primitive streak in humans remain in us in a super low quantity? For example I've read of teratomas https://www.healthline.com/health/teratoma#causes

Is it possible for these cells to still be within all of us in our tail bones yet cause no problems for the majority? Do we still have these 'primitive streak cells' in other areas of our body that don't cause problems?

Also, where does the primitive streak end at in the human body? Does a small part of it stay with us in a tiny place somewhere?


In a lab pushing the boundaries of biology, an embedded ethicist keeps scientists in check

T he young scientists had a question. They were working with mouse embryos from which all living cells had been chemically dissolved away.

So far, so good, thought the bioethicist, as she listened to the presentation at a Harvard Medical School lab meeting.

The scientists were seeding the mouse scaffolds with human stem cells. Those cells were expected to turn into human liver cells and perhaps a mini human liver and human kidney cells and perhaps mini human kidneys and human heart and brain cells and …

Jeantine Lunshof insists she is not the “ethics police.” It says so on the door to her closet-sized office at Harvard. She doesn’t find reasons to reflexively shut down experiments. She doesn’t snoop around for deviations from ethical guidelines. But when scientists discuss their research in the twice-weekly lab meetings she attends, “I will say, hmm, that raises some good questions,” Lunshof said.

There is no shortage of “good questions” for Lunshof, who for the last three years has been embedded in the synthetic biology lab of George Church, the visionary whose projects include trying to resurrect the wooly mammoth and to “write” a human genome from scratch. Church is also famous for arguing that it is ethically acceptable to edit the genomes of human embryos if doing so will safely alleviate suffering, and for encouraging people to make their full genome sequence public, privacy be damned.

In the Church lab, Lunshof told STAT, “you have incredibly interesting conversations.”


Epiblast and primitive-streak origins of the endoderm in the gastrulating chick embryo

Gastrulation is characterized by the extensive movements of cells. Fate mapping is used to follow such cell movements as they occur over time, and prospective fate maps have been constructed for several stages of the model organisms used in modern studies in developmental biology. In chick embryos, detailed fate maps have been constructed for both prospective mesodermal and ectodermal cells. However, the origin and displacement of the prospective endodermal cells during crucial periods in gastrulation remain unclear. This study had three aims. First, we determined the primitive-streak origin of the endoderm using supravital fluorescent markers, and followed the movement of the prospective endodermal cells as they dispersed to generate the definitive endodermal layer. We show that between stages 3a/b and 4, the intraembryonic definitive endoderm receives contributions mainly from the rostral half of the primitive streak, and that endodermal movements parallel those of ingressing adjacent mesodermal subdivisions. Second, the question of the epiblast origin of the endodermal layer was addressed by precisely labeling epiblast cells in a region known to give rise to prospective somitic cells, and following their movement as they underwent ingression through the primitive streak. We show that the epiblast clearly contributes prospective endodermal cells to the primitive streak, and subsequently to definitive endoderm of the area pellucida. Finally, the relationship between the hypoblast and the definitive endoderm was defined by following labeled rostral primitive-streak cells over a short period of time as they contributed to the definitive endoderm, and combining this with in situ hybridization with a riboprobe for Crescent, a marker of the hypoblast. We show that as the definitive endodermal layer is laid down, there is cell-cell intercalation at its interface with the displaced hypoblast cells. These data were used to construct detailed prospective fate maps of the endoderm in the chick embryo, delineating the origins and migrations of endodermal cells in various rostrocaudal levels of the primitive streak during key periods in early development.


Full Notes on Embryology [For Students] | Branches | Biology

Compilation of notes on embryology form the internet!

Embryology Note # 1. Introduction to Embryology:

The aim of this note is to familiarize the reader with the basic facts and problems of the science of embryology. The name “embryology” is somewhat misleading. Literally it means the study of embryos. The term “embryo” denotes the juvenile stage of an animal while it is contained in the egg (within the egg envelopes) or in the maternal body.

A young animal, once it has hatched from the egg or has been born, ceases to be an embryo and would escape from the sphere pertaining to the science of embryology, if we were to keep strictly to the exact meaning of the word. Although birth or hatching from the egg is a very important occasion in the life of the animal, it must be admitted that the processes going on in the animal’s body may not be profoundly different before and after the hatching from an egg, especially in some lower animals.

It would be artificial to limit studies of the juvenile forms of animal life to the period before the animal is hatched from the egg or is born. It is customary, therefore, to study the life history of an animal as a whole and accordingly to interpret the scope of the science of embryology as the study of the development of animals.

Embryology Note # 2. Analytical Embryology:

After the middle of the present century embryology had got caught up in the new trend that developed in biological science. Early in the century, the background for this new trend was established mainly by the work of T. H. Morgan and his school.

This work proved that the units of heredity, the genes, are arranged in linear order in the chromosomes of the cells. Analysis shows that chromosomes consist of several chemical components: deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and proteins.

In an epoch-making paper published in 1953, Watson and Crick suggested that the deoxyribonucleic acid, as found in the chromosomes, consists of pairs of very elongated molecules twisted spirally around each other in a double helix. Each strand of the helix is made up of a number of units, the mononucleotides, which differ from one another only in the nitrogenous base (i.e., adenine, thymine, guanine, or cytosine) which each contains.

The bases form two pairs, which structurally “fit” together, so that in the intertwined double helix adenine always links with thymine, and guanine with cytosine. Further work made it clear that the arrangement of the bases in the molecule of deoxyribonucleic acid contains a code for the proteins that may be synthesized by a particular species of organism.

The code is essentially a series of “triplets”—groups of three bases which correspond to one amino acid in a polypeptide (protein) chain. Thus, a sequence of triplets in the DNA determines a sequence of amino acids in a protein molecule, and the section of the deoxyribonucleic acid molecule containing this se­quence is the essential part of what geneticists call a “gene.”

Between the genetic code in the chromosomal DNA and the cell proteins, there are certain intermediate steps. The “message” contained in the DNA must first be copied in the form of a ribonucleic acid molecule, whose nucleotide sequence is complementary to the nucleotide sequence of the DNA (except that uridine takes the place of thymine). This is the “transcription” phase. The code is then contained in an RNA molecule (“messenger” RNA).

Two further kinds of ribonucleic acid are modeled on the DNA: the ribosomal RNA, which together with certain proteins forms small (± 200 Å in diameter) particles, the ribosomes and the transfer RNA, which is involved in bringing the correct amino acid to the ribosome, where the amino acids become arranged and joined together in the correct sequence according to the code contained in the mes­senger RNA. This procedure constitutes the “translation” phase.

The importance of these discoveries for embryology derives from the following considerations. It has become evident that all the properties of any organism are determined in the last instance by the sequence of base triplets in the DNA molecules. Furthermore, it is accepted that the sequence of the base triplets directly determines what kinds of proteins can be produced by an organism.

All other manifestations specific to any organism, whether morphological or physiological, depend more or less directly on the assortment of proteins coded for by the hereditary DNA. This new way of looking at the organic world shifts the problem of ontogenetic development directly into the realm of molecular relationships. It also makes possible, in principle, the construction of a complete theory of development.

Such a theory would start with the triplet sequences in the DNA and would show first how these sequences are “read out” by transforming them into an array of proteins, placed and distributed in an organized way in space and time, and then would show how the proteins, acting partly on their own and partly through other chemical components, produce the complicated system that is an adult organism.

A whole array of new techniques has been mobilized in working toward such a theory of development. Electron microscopy has made great advances after the mid 1950’s, when methods were developed for embedding tissues in plastics and for cutting ultrathin sections for the study of the fine structure of cells. Refined methods of chemical analysis, such as chromatography, electrophoresis, ultracentrifugation, and the use of radioactive tracers, have been put at the disposal of embryologists.

With the change in the theoretical background and techniques, a subtle change has permeated the work of embryologists. The aim of investigation is no longer the study of the development of any particular animal, or any group of animals, but the discovery of the basic principles and processes of development. This trend in science may perhaps be called analytical embryology, and this is what “modern” embryology actually is.

It must be realized that analytical embryology can proceed only on the basis of knowledge provided by descriptive embryology, because after all, it is the actual course of the transformations that has to be explained by the theory of development, of comparative embryology, because it is necessary to know of how general a significance any particular phenomenon of development is, and of experimental embryology, because it has revealed the causal relationships of many developmental processes.

Embryology Note # 3. Structure and Functions of Nuclei Acids:

The structure and function of nucleic acids and their role in controlling the synthesis of proteins—which is the subject of the branch of science referred to as “molecular biology” in the narrow sense of the term—has been elucidated in the first instance by work done on bacteria and viruses.

These forms of life (together with blue-green algae) are considered as belonging to the Prokaryota—forms of life without true nuclei. The animals, multicellular animals in particular, belong to the nucleated organisms, the Eukaryota.

In recent years it has become clear that the structure and functions of the nucleic acids in eukaryotes differ in many essential features from those in prokaryotes, and that results obtained in work on the prokaryotes cannot be used directly for explaining the vital processes in eukaryotes, and especially the processes of morphogenesis.

There is a deep-seated difference in the very tasks that the nucleic acid-protein mechanisms have to fulfill in prokaryotes and the eukaryotes. In prokaryotes the DNA (or RNA in some viruses) serves to transmit heredity and to control vital processes in one type of cell only.

In multicellular animals (and plants), in addition to transmitting hereditary traits and controlling the vital processes of a general nature, the mechanism embodied in the DNA provides for the elaboration of a complex system in which different parts perform a variety of different functions. This inevitably calls for a more complex organization of the genome and for a system of functions which are non­-existent in prokaryotes.

Embryology Note # 4. Cells in Seminiferous Tubules:

The development of the spermatozoa takes place in the male gonads, the testes. In vertebrates and insects, the testes are composite organs consisting of numerous semi­niferous tubules, or seminiferous lobules, converging toward common ducts which lead the mature sperm to the exterior.

Spermatogenesis is a continuous process, and various stages of development of the sperm may be observed in the seminiferous tubules at the same time. In the tubule there is, however, an orderly arrangement of cells undergoing different phases of de­velopment.

In insects, the proximal ends of the tubules contain the spermatogonia— the cells undergoing proliferation by mitosis. Further down the tubule, the cells in the growth and maturation stages (the spermatocytes) are found. The ripe spermatozoa fill the most distal parts of the tubules.

In vertebrates, the arrangement of the cells in the seminiferous tubules is somewhat different – all stages, from spermatogonia to mature spermatozoa, may be found at the same level of the tubule, but while the early stages (the spermatogonia) are located at the outer surface of the tubule in an epithelium-like arrangement next to the basement membrane, the later stages of differentiation, in­cluding ripe spermatozoa, lie nearer to the lumen of the tubule.

A special feature in the testes of vertebrates is the presence in the seminiferous tubules of somatic cells, which assist the developing spermatozoa by anchoring the dif­ferentiating cells and possibly nourishing them during the latter part of sperm develop­ment.

These cells, known as Sertoli cells, are tall columnar cells attached proximally to the basement membrane and reaching distally to the lumen of the tubule. The Sertoli cells have large pale nuclei with conspicuous nucleoli, thus differing from the rather dense chromatin-rich nuclei of spermatogonia and spermatocytes.

The cells differen­tiating into spermatozoa become partially embedded in the cytoplasm of the Sertoli cells, the future heads of the spermatozoa pointing toward the base of the Sertoli cells and the tails growing out toward the lumen of the semini­ferous tubule. There are no Sertoli cells in the seminiferous tubules of insects, but similar cells are found in the testes of molluscs.

The spermatogonia, as already stated, are found in vertebrates next to the basal membranes of the seminiferous tubules, and in microscopic preparations many of these may be seen to be in mitosis. While part of the spermatogonia remain in this con­dition and form a source of new sex cells throughout the reproductive life of the animal, some of the cells which are produced move toward the lumen of the tubule and enter the next phase of spermatogenesis: the phase of growth.

The cells in this stage are called primary spermatocytes. The growth of the spermatocytes is actually very limit­ed, though as a result they become perceptibly larger in volume than the spermatogo­nia (roughly by a factor of 2). However, the main feature of these cells is that they enter into the prophase of meiotic divisions which are of the greatest importance in the reproductive cycle of all organisms, but which can be dealt with only in their essentials here.

Embryology Note # 5. Cleavage:

One of the peculiarities of sexual reproduction in animals is that the complex multicellular body of the offspring originates from a single cell—the fertilized egg. It is necessary, therefore, that the single cell be transformed into a multicellular body. This transformation takes place at the very beginning of development and is attained by means of a number of cell divisions following in rapid succession. This series of cell divisions is known as the process of cleavage.

Cleavage can be characterized as that period of development in which:

1. The unicellular fertilized egg is transformed by consecutive mitotic divisions into a multicellular complex.

3. The general shape of the embryo does not change, except for the formation of a cavity in the interior—the blastocoele.

4. Apart from transformation of cytoplasmic substances into nuclear substance, qualitative changes in the chemical composition of the embryo in cleavage are limited.

5. The constituent parts of the cytoplasm of the egg are not displaced to any great extent and remain on the whole in the same positions as in the egg at the beginning of cleavage.

6. The ratio of nucleus to cytoplasm, very low at the beginning of cleavage, is, at the end, brought to the level found in ordinary somatic cells.

Embryology Note # 6. Metamorphosis:

The first case in which morphogenetic processes may be reactivated after develop­ment has almost reached a standstill is observed in animals in which the embryo develops into a larva, and the larva is transformed into the adult by way of metamorphosis. Larval forms and an accompanying metamorphosis are found in most groups of the animal kingdom, though by no means in all representatives of each group. The larvae usually have special names distinguishing them from the adult forms.

Final Remarks on Metamorphosis:

The metamorphosis of amphibians and insects is an excellent example of the control of morphogenetic processes by hormones. The dependence of differentiation on diffusible chemical substances, as revealed in studies on metamorphosis, should be compared with the results of experiments on the influence of diffusible substances on the differentiation of cells in tissue cultures.

When comparing the interrelation of different hormones in insect and amphibian metamorphosis, one is astonished to find that these two groups of animals have developed causative mechanisms having a distinct general similarity. In both cases, the transformation is initiated by a secreting organ closely associated with the brain – the hypophysis in amphibians, the neuro-secretory cells of the proto-cerebrum in insects.

In both cases, the secretion of this primary center does not act on the tissues directly but stimulates the activity of a second endocrine gland – the thyroid gland in amphibians, the prothoracic gland in insects. Lastly, the juvenile hormone of insects which has the function of checking and preventing precocious metamorphosis has an equivalent in the prolactin-like hormone of frog tadpoles.

There is very little information as to the causative agents of metamorphosis in animals other than amphibians and insects, and we do not know whether their trans­formations are controlled by hormones. One would expect that at least in the cyclostomes the transformation of the larva (ammocoete) into the adult should be caused by hormones, but this has not been found to be the case thyroxine does not accelerate transformation of the ammocoete into a lamprey.

In the ascidian tadpole, the absorption of the tail is in some way dependent on the anterior end of the body, since cutting off the anterior tip with the adhesive papillae will prevent the necrotization of the tail. Treating ascidian tadpoles with thyroid hormone accelerates the metamorphosis, but this action is hardly specific, as the tadpole does not have a thyroid gland of its own and treatment of the tadpoles with narcotics or even with distilled water has the same effect.

Numerous experiments have been carried out on the metamorphosis of larvae of various invertebrates (Tubularia, Bryozoa, sea urchins, molluscs). Treatment by various chemicals (e.g., salts of copper) has had a positive effect. However, it has not been possible to find what factors cause the metamorphosis under normal conditions, and there is so far no indication that in any of these organisms a hormone plays a decisive role in the process.

An exception to the statement is apparently presented by the transformation of the asexual form of the annelid worm, Platynereis dumerilii, into the sexual form. This transformation is dependent on a neuro-secretory hormone released in the prostomium of the asexual individual. The hormone is an inhibitor of the transformation, and the sexual form is developed when the prostomium hormone is eliminated.

Embryology Note # 7. Growth of Individual Cells:

Growth of individual cells is the most essential component of the growth of multi­cellular bodies. It is therefore of some importance to know the quantitative charac­teristic of cell growth. Unfortunately, because of the size of cells, measuring the growth of individual tissue cells is very difficult, although the rhythm of cell multiplication, espe­cially in vitro in tissue cultures, can be observed quite easily.

Actual measurements of growth of single cells between two mitoses have been made on unicellular organisms. The growth of infusorians with elongated bodies was studied by measuring their length at regular intervals between two divisions, and in a heliozoan, Actinophiys, which has a spherical shape the growth was estimated by measuring the diameter of the cell.

Increase in weight of individual cells is even more difficult to measure. However, by means of a very fine technique, the weighing of individual cells of Amoeba throughout its life cycle has been accomplished. The results of all these measurements conform well with one another and show that in these unicellu­lar organisms growth is most rapid after a cell division and slows down later.

It is reasonable to assume that the course of growth of cells in multicellular organisms follows the same general course this, however, is an extrapolation which needs further experimental confirmation.

Embryology Note # 8. Review of Placentae in Different Groups of Mammals:

Differences in placentae of various mammals are caused in part by the structure and arrangement of the villi and in part by the degree of connection between the maternal and fetal tissues. In the more primitive Eutherian mammals the placentae are non-deciduous.

The villi may be scattered all over the surface of the chorion, in the case of the pig, and this type of placenta is known as the diffuse placenta. In cattle, the villi are found in groups or patches, while the rest of the chorion surface is smooth. The patches of villi are called cotyledons, and a placenta of this type is known as the cotyledon placenta.

In carnivores, the villi are developed in the form of a belt around the middle of the blastocyst, which is more or less elliptical in shape. This is the zonary placenta. In man and the anthropoid apes, the chorion is, at first, all covered with villi, but the villi continue developing only on one side, the side turned away from the lumen of the uterus, while on other parts of the chorion the villi are reduced.

The functional placenta therefore has the shape of a disc and is known as the discoidal placenta. A discoidal placenta has also been developed independently in the rodents (mouse, rat, rabbit, and others). In the monkeys, the placenta consists of two discs—a bidiscoidal placenta.

The thickness of the partition between the maternal and fetal blood may be diminished by the removal of some of the intervening layers of tissue. Depending on which layers have disappeared, several types of placentae may be distinguished. The names given to the various types indicate the two tissues—one maternal, the other-fetal—which are in immediate contact.

In the more primitive cases, the following layers of tissue participate in the diffusion of substances from the mother to the embryo:

1. The blood of the mother.

2. The endothelial wall of the maternal blood vessels.

3. The connective tissue around the maternal blood vessels.

5. The epithelium of the chorion.

6. The connective tissue of the chorion.

7. The endothelial wall of the blood vessels in the chorion.

8. The blood of the embryo.

If all these tissues are present in the placenta, the chorionic epithelium is in contact with the uterine epithelium, and the placenta is designated as an epitheliochorial placenta. This type of placenta is found in all marsupials and in the ungulates (horses, pigs, cattle). In the case of an epitheliochorial placenta the villi, in their growth, push in the wall of the uterus and later lie in pocket-like depressions of the uterine wall.

When the blastocyst is implanted and, subsequently, when the villi begin to grow, the superficial tissues of the uterine wall may be destroyed to a greater or lesser extent. If the destruction involves the uterine epithelium and the underlying connective tissue, the epithelium of the chorion may come into direct contact with the endothelial walls of the maternal capillaries. A placenta is then formed which is called an endotheliochorial placenta. It is found mainly in carnivores but also in a few other mammals.

The destruction of the maternal tissues of the uterine wall may involve the en­dothelium of the maternal blood vessels. The cavities of the blood vessels are then opened up, and the villi of the chorion become bathed in the maternal blood, thus facilitating gas exchange and diffusion of nutrient substances from the maternal blood into the blood vessels of the chorionic villi.

This type of placenta, the hemochorial placenta, is found in primates and in many insectivores, bats, and rodents. Actually, the chorionic villi are surrounded by spaces (sinuses) devoid of an endothelial lining, into which maternal blood enters through the arteries of the uterus and from which the blood flows into the uterine veins. The villi may be ramified dendritic structures, or they may coalesce distally and form a more or less complicated network.

In the case of epitheliochorial placentae, at parturition the villi can be pulled out of the pockets in which they have been embedded, and the fetal part of the placenta may be removed, leaving the surface of the uterine wall intact. There is therefore no bleeding at birth.

This is not the case with other types of placentae at parturition not only the fetal component of the placenta is shed but also a part of the uterine wall participating in the function of the placenta is torn away. An open wound is left on the wall of the uterus, and hemorrhage inevitably occurs. In the latter case the placenta is said to be deciduous, whereas in the first case the placenta is non-deciduous.

The hemorrhage at parturition is normally stopped by the same mechanism that serves for the expulsion of the newborn – the contraction of the muscular wall of the uterus constricts the blood vessels and thus slows down the flow of blood, until clotting of the blood stops the hemorrhage altogether.

Embryology Note # 9. Physiology of the Placenta in Mammals:

In the absence of yolk in mammalian eggs, the nutrition of the mammalian embryo in the uterus is wholly dependent on the flow of supplies from the maternal body via the placenta, hence the close connections between the fetal and the maternal tissues. Nevertheless, the fetal and maternal tissues in the placenta do not blend together.

It cannot be stressed too much that the blood of the mother and that of the embryo do not mix under normal conditions the maternal blood does not enter the blood circulation of the embryo or vice versa. Between the maternal and the fetal blood there exists a separation—the placental barrier.

Physically, the barrier consists of the tissue lying between the blood spaces in the embryonic and maternal parts of the placenta this barrier may be attenuated (as in hemochorial placentae) but is not broken down. Physiologically the placental barrier is like a semi-permeable membrane, allowing some substances to pass through but keeping out others.

Small molecule substances pass through the placental barrier by simple diffusion. This applies to water, oxygen passing from the maternal into the fetal blood, carbon dioxide and urea passing from fetal to maternal blood, simple salts of sodium potassium and magnesium, and mono-saccharides.

Active transport of some form or another participates, however, in the penetration of more complex substances through the placental barrier. It is a well-established fact that vitamins and hormones may pass from the mother to the fetus. Passage of some very complex substances, proteins in particu­lar, may perhaps be affected by pinocytosis at the surface of the trophoblast.

Highly complex proteins are known to be able to penetrate the placental barrier. In this way antibodies, which have developed in the blood of a mother who has acquired immunity to certain diseases, such as diphtheria, scarlet fever, smallpox, and measles, are passed to the fetus, which thus becomes passively immunized and unsusceptible to these illnesses in the first period after birth.

It is worth noting that in cows, which have an epitheliochorial placenta and thus a formidable placental barrier, antibodies cannot be passed from mother to offspring through the placenta but, instead, are supplied to the newborn animal in colostrum milk after birth.

Certain pathogenic organisms and viruses-are able to penetrate through the placental barrier and infect the fetus if the mother is infected. Such penetration is known to happen with syphilis (causing congenital disease) and also in infections with smallpox, chickenpox, and measles. One virus infection which has been found to be very danger­ous for the embryo is rubella, or German measles.

Many drugs used medicinally may penetrate the placental barrier and may some­times cause most adverse effects on the embryo. Thus it is believed that the drug thalidomide, which was used as a sedative, when taken by women in early pregnancy (25 to 44 days), caused extensive deficiencies in the development of limbs, the alimen­tary canal (non-perforation of the anus), and the heart.

Lastly, it must be pointed out that although the tissues of the mother and fetus, including the trophoblast, do not mix and the blood streams of the two are held apart, occasional penetration of individual cells across the placental barrier is not an excep­tional occurrence.

Small numbers of fetal blood corpuscles are sometimes found in the maternal circulation as well as maternal corpuscles in the circulation of the embryo. This may be the result of accidental breakage of the respective blood capillaries. The origin of the corpuscles can be verified since the fetal erythrocytes are nucleated and the erythrocytes of the adult female are without nuclei.

Small fragments of the trophoblast may become detached from the chorionic villi and may be carried away by the maternal blood stream they are later found in the blood capillaries of maternal organs, such as the lungs. On the other hand, maternal cells, probably white blood corpuscles, have been found lodged in the lymphatic system (spleen, thymus, lymph nodes, and bone marrow) of the fetus.

Embryology Note # 10. Repetitive DNA Sequences:

The genes in the DNA enumerated so far do not by any means constitute the whole of the chromatin in a eukaryotic cell. If the DNA of such a cell is broken up into fragments of varying length, and the fragments are allowed to hybridize, it is found that there are numerous fragments that hybridize quickly, which means that they can easily find corresponding (complementary) partners.

This in turn means that there are large numbers of repetitive (identical) DNA sequences in the genome. Some, but not all, of these repetitive sequences are the ones coding for rRNA and tRNA. There are very large numbers of short (200 to 500 nucleotides in length) sequences, the function of which is not known at present.

In the rat genome it has been claimed that 70-75 per cent of the DNA is in unique sequences (presumably coding for mRNA), that 15-20 per cent of the DNA is repeated 10 to 100,000 times (the rDNA and tDNA genes fall into this category), and that 6 per cent of the DNA consists of sequences that are repeated more than 100,000 times.

There is good reason to suspect that these repetitive sequences serve somehow to control and regulate the functioning of the genes of the genome. Furthermore, there is a special class of eukaryotic DNA that in re-association experiments tends to fold back upon itself and form double-stranded hairpin loops.

This is the result of the presence in the DNA chromatin of base sequences that are arranged in a reverse order (“palin­drome” sequences, like words and sentences which read the same back to front). There is some evidence that these loops provide recognition sites in some nucleic acid-protein interactions.

Finally, very short (6-15 nucleotides in length) repetitive DNA sequences, which are neither transcribed nor translated, are grouped in enormous numbers repeated 10 3 to 10 7 times in the centromere region of eukaryotic chromosomes.

Embryology Note # 11. Process of Induction and Differentiation of Cell:

The physicochemical nature of the processes of induction concerns the way in which the inducing substances control the differentiation of cells. In principle it may be assumed that the inducing substances penetrate into the cells and, by interfering in the metabolic mechanisms in the interior of the cells, change their physicochemical composition. Although this mechanism of action seems to be fairly plausible, it is not self-evident.

Radioactive tracers have been used to learn whether, in the process of embryonic induction, substances pass from the inducing tissue into the reacting tissue. Labeled amino acids, methionine 35 S and glycine 14 C, and a nucleic acid precursor, orotic acid 14 C, were used in some experiments. These compounds are taken up into the tissues of the embryo.

Next, inducing parts—roof of the archenteron or parts of brain rudiments—are excised from the embryo containing radioactive substances and are transplanted into a normal embryo where the graft may induce neural plates or other structures from the host tissue. The embryo is then fixed and cut into sections, and autoradiographs are prepared.

It has been found that the radioactive atoms do not remain restricted to the cells of the grafts, but that they become fairly widely dispersed in the host embryo. A high radioactivity is shown by induced neural plates, which may be the result of the passage of inducing substances from the graft into the host tissue.

However, the host neural plates and tubes are also strongly radioactive, and radioactivity can also be discovered in the mesodermal and endodermal tissues of the host. These results are consistent with the assumption that the radioactive atoms are carried around in the host tissue by simple diffusion.

Furthermore, it cannot be claimed with certainty that the diffusing substance was actually the macromolecular material which can reasonably be assumed to be the inducing agent. It could well be that the radioactive atoms were carried around as components of small molecules (single amino acids, mononucleotides, and even smaller organic and inorganic molecules).

The preceding criticism does not apply to another set of experiments in which use was made of immunological methods to trace the passage of substances from the inductor into the reacting tissue. Antibodies were prepared against malignant tumor tissue used in one experiment and against a purified protein preparation isolated from guinea pig bone marrow in another experiment.

The antibodies in the antiserum were later coupled to a fluorescent dye, rhodamine B 200. Triturus ectoderm was exposed to the action of the inductor (tumor tissue in one case, protein preparation in the other) for a few hours, then fixed, and cut into sections. The sections were then treated with the antiserum coupled with the fluorescent dye.

Owing to antigen-antibody binding, the antibody molecules with the attached dye became localized in the section in positions which indicated the distribution of the antigen molecules (the molecules of the inductor). The fluorescent dye made these locations easily discernible. Distinct fluorescence was found in the reacting tissue, thus showing that antigen molecules had actually penetrated into it.

Since the specificity of the antibody-antigen reaction would have disappeared if the antigen molecules were degraded to any great extent, it is evident that the macromolecules of the materials used as inductors penetrated into the reacting cells without being split up into small components.

As a final proof, a radioactively labeled “mesodermalizing factor” was prepared, and it was found to actually enter the cells exposed to this factor.

An attempt was made to see whether the purified “mesodermalizing factor” binds to DNA. The results were inconclusive. The possibility remains, therefore, that there exists in the cells of the gastrula some kind of “receptor” molecules which interact with the inducing substance and mediate its influence on the genome of the reacting cells.

Some evidence on the mechanism of induction has been provided by the use of metabolic poisons coupled with induction experiments. If the induction is mediated by the diffusion of some specific proteins (or nucleoproteins) from the inducing to the reacting tissue, then it may be postulated that a specific protein has been manufactured in the inductor at some stage and that a corresponding mRNA had been transcribed from a locus on the DNA.

Secondly, if the reacting tissue acquires new properties, this, in all probability, means that some new substances have been produced in the reacting cells or that existing substances have been modified. In both cases, it would be suspected that new proteins are involved, a circumstance which again presupposes transcription of a new kind of mRNA and translation into a previously absent new protein.

That the change is caused simply by the presence in the reacting cells of the inducing substance, which had passed into them from the inductor, is highly improb­able, especially in view of the possibility of neural induction by way of sublethal cytolysis.

The synthetic mechanisms of the reacting cells are obviously involved in the transforma­tion. Consequently, the question is, what would happen to the process of induction if transcription or translation were prevented in the inductor, or in the reacting tissue, or in both?

In some experiments the dorsal blasto­pore lips of young Triturus gastrulae were cultivated for up to 20 hours in a medium containing actinomycin D or puromycin, and then the explant was confronted with reacting ectoderm. Mesodermal induction or both mesodermal and neural inductions were obtained.

These results prove that neither transcription of mRNA nor synthesis of new proteins occurs in the inductor at the time of its action that is, the inducing substance is already present at the beginning of gastrulation (which could be expected, since a killed inductor can induce).

If, on the other hand, the dorsal blastopore lip was explanted with the adjacent ectoderm and cultivated in a medium containing sufficient quantities of actionomycin D to inhibit RNA synthesis completely, induction could not take place. After two to seven days of cultivation it was found that while some differentiation of muscle and notochord occurred, there was no differentiation of nervous tissue.

Since no new mRNA could be produced under the circumstances, it follows that the mRNA for notochord and muscle differentiation was already present at the time of explantation— at the beginning of gastrulation. For the ectoderm to start neural differentiation, how­ever, it was necessary for the reacting cells to produce new mRNA by transcription from the DNA in the reacting cells. Such transcription was made impossible by the presence of actinomycin D, and the result was that no neural induction could be detected.

Lastly, Triturus gastrula ectoderm, which was exposed to an inductor in a “sandwich” experiment, was separated from the inductor and treated with actinomycin D for six hours, after having been disaggregated to allow better penetration of the poison into the cells.

In controls, the dis-aggregated cells fused together again and differentiated into neural and mesodermal tissues, as would be expected in view of the inductor which had been used – Actinomycin-treated explants also re-aggregated and remained viable for days, but only atypical epidermal differentiation took place.

This experiment shows that even though an “inducing substance” may have penetrated into reactive cells, their transformation into differentiated neural and mesodermal cells cannot occur without active participation of the nuclei of reacting cells, and particularly without an RNA (presumably mRNA) being produced as a crucial link in the process of induction.

Embryology Note # 12. General Body Form of Vertebrates:

While the various organs are being formed, the shape of the embryo as a whole undergoes far-reaching changes.

During the period of organogenesis, in the case of the vertebrate embryo, the main changes are:

3. Subdivision of the body into head and trunk.

4. Development of appendages.

5. Separation of the embryo proper from the extra embryonic parts.

Some of the processes just enumerated also occur in invertebrates in particular, the elongation of the body occurs in annelids and arthropods. The sub-division of the body into sections, such as the head, thorax, and abdomen, is typical of insects and, with modifications, of some other arthropods.

The development of appendages is an essen­tial feature of arthropod development. Other processes concerning the body as a whole may occur in invertebrates but have no counterpart in vertebrate development. For instance, in insects the body of the embryo undergoes a peculiar shifting from the surface of the egg into the interior of the yolk, from which it emerges again at a later stage.

In holoblastic vertebrates, of which the amphibians may serve as an example, the embryo retains a spherical shape (i. e., the shape possessed by the unfertilized egg) up to the end of gastrulation and the beginning of neurulation. In the neurula stage the embryo becomes slightly elongated in an anteroposterior direction, but only after the completion of neurulation does the elongation of the embryo become prominent.

A tail rudiment, the tail-bud, appears at the posterior end of the body and rapidly develops into an elongated appendage, but the rest of the body also stretches, becoming at the same time flattened laterally and, to a certain extent, lower in a dorsoventral direction.

Although most of the organ rudiments of the embryo are involved in this elonga­tion, there is experimental evidence that not all are equally active. If the notochordal rudiment of an amphibian embryo in the neurula stage is excised, the embryo remains stunted and does not stretch as usual.

On the other hand, the notochordal rudiment will stretch and form an elongated rod even if it is cultivated in vitro and is not accompanied by other parts. Isolated parts of the neural system or induced brain vesicles, when no other tissues accompany them, fail to elongate.

From these facts it appears that the notochord changes its shape actively, while the nervous system is pulled in length by the adjacent notochord. In amniotes the elongation starts in the primitive streak stage, so that the body of the embryo is already long and narrow by the time the main axial organs (neural tube, notochord, dorsal mesoderm giving rise to the somites) are laid down.

In terrestrial vertebrates the sub-division of the body into the head and trunk is largely dependent on the reduction of the branchial apparatus. The system of visceral clefts and arches is fully developed in embryos of all vertebrates.

In fishes and the larvae of amphibians, the visceral clefts and arches persist and take up the area on the ventral side and posterior to the head. In terrestrial vertebrates, the branchial apparatus loses its respiratory function and becomes reduced. As a result, in later embryonic stages the area of the body posterior to the head fails to grow at the same rate as the other parts, thus producing a constricted section between the head and trunk.

The constriction is accentuated further by:

(a) A certain amount of longitudinal stretching of the neck region, as a result of which the cervical vertebrae are, as a rule, somewhat longer than thoracic vertebrae (not true in some mammals with shortened necks, such as man or the whales) and

(b) The withdrawal of the heart, originally situated in the neck region next to the branchial clefts, into the trunk (thorax).


Human embryonic stem cells get organized

Olivier Pourquié is in the Department of Genetics, Harvard Medical School, and in the Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA.

You can also search for this author in PubMed Google Scholar

In 1924, Hilde Mangold and Hans Spemann performed what became one of the most famous experiments in developmental biology. They grafted various parts of a pigmented salamander embryo onto an unpigmented host embryo, and showed that one grafted region induced unpigmented cells from the host to form an extra embryo, resulting in a ‘double embryo’ reminiscent of conjoined twins 1 (Fig. 1a). The duo named the grafted region the organizer, because of its extraordinary ability to organize the host cells around it. But in the almost 100 years since this experiment, technical and ethical difficulties have prevented researchers from demonstrating the presence of an organizer in human embryos. In a paper in Nature, Martyn et al. 2 use stem cells to circumvent these challenges and provide the first experimental description of the human organizer.

Figure 1 | Experimental demonstration of organizer structures. a, In 1924, an experiment 1 revealed the properties of an embryonic structure called the organizer. When taken from a pigmented salamander embryo and grafted onto an unpigmented host, the organizer induced the formation of a second embryo derived from unpigmented host cells. b, Martyn et al. 2 have demonstrated the existence of human cells endowed with similar properties, using human embryonic stem (ES) cells. The authors treated circular discs of ES cells with the growth-factor proteins Wnt and Activin to produce organizer-like cells (blue). When the discs are grafted onto the extra-embryonic tissue around a chick embryo, they induce the host tissue to form an elongated stretch of neural tissue — the standard test for organizer properties.

To fully understand the importance of the organizer, we must go back to the earliest stages of embryonic development. In vertebrates, the fertilized egg rapidly divides to form a ball of poorly organized cells. At a particular developmental time point, some cells on the surface of this ball become internalized, forming tissues called the endoderm and the mesoderm, which respectively give rise to the gut and to muscles and the skeleton. Other cells remain external and give rise to the skin and the nervous system. This fundamental process of internalization is called gastrulation.

The organizer lies immediately adjacent to the site at which cells become internalized during gastrulation. It gives rise to specific tissues lying along the midline of the embryo, including the notochord — a structure that controls aspects of development of the central nervous system and eventually contributes to the intervertebral discs. An equivalent of the salamander organizer has been found in fish and birds and in mammals such as rodents 3 . In mammals, the structure that acts as an organizer is called the node because it resembles a knot, and the site of internalization is called the primitive streak.

Unlike salamander embryos, mammals develop in the mother’s womb. Accessing and culturing mammalian embryos is therefore difficult. Indeed, it wasn’t until 1994 that grafts of a mouse node into a host embryo provided experimental proof of the existence of a structure that has organizer properties in mammals 4 . Although no perfect second embryos were formed in these experiments, the grafted nodes did induce the formation of host-derived neural tissues and sometimes other embryonic tissues.

Read the paper: Self-organization of a human organizer by combined Wnt and Nodal signalling

Human embryos greatly resemble mouse embryos and contain a structure that looks similar to the mouse node 4 . Theoretically, showing that this structure does indeed have the role of an organizer would require researchers to access embryos at three weeks of age (when gastrulation occurs), to graft the node onto a host embryo, and to test whether it induces the formation of a host-derived nervous system and skeletal structures. However, obtaining intact human embryos at this stage, for example from a pregnancy termination, is extremely problematic. Thus, whether the node represents a functional organizer in human embryos has remained unproven.

One alternative would be to let embryos obtained from in vitro fertilization (IVF) develop in culture until the three-week stage, when the node should be present. However, following an ethical consensus that is enshrined in law in many countries, human embryos cannot be cultured in vitro beyond 14 days, making these studies currently impossible.

A second alternative involves the use of pluripotent stem cells, which can give rise to all the body’s cell lineages. Protocols to direct in vitro differentiation of these cells make it possible to recapitulate several aspects of embryonic development in a culture dish.

Pluripotent cells derived from human embryos, called embryonic stem (ES) cells, generally form poorly organized colonies when grown in culture. However, the group that performed the current study previously induced 5 ES cells to self-organize in a way that resembles early embryonic development. They achieved this by culturing the cells on circular micropatterns (microprinted discs of a material called extracellular matrix that is an optimal substrate for the cells) in the presence of the growth factor protein BMP4. The cultures formed endoderm and mesoderm but did not produce primitive streaks or node-like structures.

Martyn et al. took this strategy a step further. They successfully differentiated human ES cells into a node-like tissue by treating their micropatterned cultures with a combination of the growth factors Wnt and Activin, which are crucial for primitive streak and node formation in mice and other vertebrates 6 , 7 . This treatment led to the formation of a structure that showed characteristics of a primitive streak and to the induction of cells that produced organizer-specific proteins, such as Goosecoid 8 .

To test whether this structure also has the functional characteristics of an organizer, the authors grafted its cells onto chicken embryos, in an area destined to give rise to extra-embryonic tissues that support embryonic development. Remarkably, the grafted cells organized into a notochord-like tissue and induced host cells to form elongated neural tissue (Fig. 1b), demonstrating that the grafted structure has the properties of an organizer.

One could argue that these experiments still raise ethical concerns because they are performed using human ES cells derived from an early-stage human embryo. However, pluripotent cells generated by reprogramming adult cells, which have essentially identical properties to ES cells, could be used as an alternative, alleviating this concern in future studies.

Martyn and colleagues’ experimental system provides an alternative to using embryos to study the human embryonic node. Moreover, their experiments suggest that there is striking evolutionary conservation of organizer function from fish to humans. How the organizer organizes the surrounding embryonic tissues into an embryo remains poorly understood, for now at least. But the ability to produce organizer tissue in unlimited amounts in vitro will allow researchers to dissect organizer function at an unprecedented level.

Nature 558, 35-36 (2018)


Conclusions

Our results highlight the experimental possibilities provided by differentiating ESC as a first approximation to understanding the mechanisms underlying events that, like gastrulation, are difficult to access in the embryo. Having established the similarities between the two systems, it will be important to exploit them to see how one could reproduce the primitive streak in culture through, for example, confining the movement of differentiating ESCs and attempting to create directionality by imposing spatially constrained forces.


Reprogramming to pluripotency does not require transition through a primitive streak-like state

Pluripotency can be induced in vitro from adult somatic mammalian cells by enforced expression of defined transcription factors regulating and initiating the pluripotency network. Despite the substantial advances over the last decade to improve the efficiency of direct reprogramming, exact mechanisms underlying the conversion into the pluripotent stem cell state are still vaguely understood. Several studies suggested that induced pluripotency follows reversed embryonic development. For somatic cells of mesodermal and endodermal origin that would require the transition through a Primitive streak-like state, which would necessarily require an Eomesodermin (Eomes) expressing intermediate. We analyzed reprogramming in human and mouse cells of mesodermal as well as ectodermal origin by thorough marker gene analyses in combination with genetic reporters, conditional loss of function and stable fate-labeling for the broad primitive streak marker Eomes. We unambiguously demonstrate that induced pluripotency is not dependent on a transient primitive streak-like stage and thus does not represent reversal of mesendodermal development in vivo.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Upregulation of primitive streak and…

Upregulation of primitive streak and mesendoderm markers during reprogramming of human somatic cells…

EOMES protein is not detectable…

EOMES protein is not detectable during several stages of murine fibroblast reprogramming. (…

Eomes protein remains absent upon…

Eomes protein remains absent upon lineage tracing during MEF reprogramming. ( A )…

Eomes is dispensable for reprogramming…

Eomes is dispensable for reprogramming of murine fibroblasts. ( A ) Schematic illustration…


Footnotes

† Present address: Institute of Cancer Research, 123 Old Brompton Road, London SW7 3RP, UK.

Electronic supplementary material is available online at https://doi.org/10.6084/m9.figshare.c.4829343.

Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

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Molecular

  • Prdm1 and Prdm14 - PR domain proteins expressed in mouse (E6.25), suppresses somatic differentiation.
  • Sall4 - zinc finger protein, inactivation of this transcription factor in mouse can reduce PGC number. ⎗]

A study has recently identified 11 genes that are specifically expressed in male and female fetal germ cells, both in vivo and in vitro, but are not expressed in embryonic stem cells. ⎣]


PGC Markers: alkaline phosphatase-positive, Oct4 (POU5F1), Fragilis (IFITM1) ⎤] , Stella (DPPA3), Dazl, and Vasa (DDX4).

  • Steel factor - (KITLG) a ligand for the KIT tyrosine kinase receptor.
  • dead end - coding an RNA binding protein mainly expressed in the germ cells of vertebrates.
  • Blimp1 - B-Lymphocyte induced maturation protein-1 (PRDM1)
  • Prmt5 - protein arginine methyltransferase-5
  • Nanog - knockdown induces apoptotic cell death in mouse migrating primordial germ cells. ⎥]
  • AID - Activation-Induced cytidine Deaminase enzyme required for demethylation (removal of CpG methylation). Within the genome, DNA methylation is associated with epigenetic mechanisms and occurs at cytosine residues that are followed by guanines. ⎦]

Stem Cells

A recent study in chicken has shown that only two key factors are required to convert stem cells into haploid spermatids: ⎧]


INTRODUCTION

Mammals are unlike most other animals in that the small zygote requires substantial cell proliferation before the elaboration of a basic body plan can begin. During the growth of the early embryo, individual cells must retain the ability to make all adult cell types, i.e. pluripotency. Understanding mechanisms that control pluripotency is an important goal of stem cell research and was stimulated by the discovery of conditions enabling embryonic stem cell (ESC) cultures to be derived from outgrowths of the blastocyst inner cell mass (ICM) (Evans and Kaufman, 1981 Martin, 1981).

In vitro experiments with ESCs showed that the Oct4 (Pou5f1 - Mouse Genome Informatics), Sox2 and Nanog transcription factors constitute core components of a gene regulatory network (GRN) that stimulates self-renewal of pluripotent cells. The GRN model is supported by overlapping sites of chromatin occupancy for Oct4, Sox2 and Nanog proteins, including on one another’s genes (Boyer et al., 2005 Cole et al., 2008 Loh et al., 2006 Marson et al., 2008), and extensive protein-protein interactions between the three factors (Chambers and Tomlinson, 2009 Kim et al., 2008 Liang et al., 2008 Wang et al., 2006). Tcf7l1 (formerly Tcf3) has been identified as a crucial regulator of the pluripotency GRN in ESCs by studies showing that Tcf7l1 co-occupies Oct4, Sox2 and Nanog sites in chromatin (Cole et al., 2008 Marson et al., 2008 Tam et al., 2008) and that Tcf7l1 regulates the expression of Oct4 and Nanog target genes (Cole et al., 2008 Pereira et al., 2006 Tam et al., 2008 Yi et al., 2008). Recently, the Esrrb transcription factor was identified as a direct target of Tcf7l1 regulation important for Tcf7l1-mediated effects on self-renewal in vitro (Martello et al., 2012).

Whereas Esrrb, Oct4, Sox2 and Nanog all stimulate self-renewal, genetic experiments unequivocally show that Tcf7l1 inhibits self-renewal (Guo et al., 2011 Pereira et al., 2006 Salomonis et al., 2010 Wray et al., 2011 Yi et al., 2011 Yi et al., 2008). Interestingly, Tcf7l1 is a transcriptional repressor in the Wnt/β-catenin pathway (Wu et al., 2012), and Wnt activity is necessary for mouse ESC self-renewal (ten Berge et al., 2011). Ablating Tcf7l1 is sufficient to replace a requirement for Wnt/β-catenin signaling, indicating that endogenous Tcf7l1 expression causes ESC dependence on Wnt/β-catenin (Wray et al., 2011 Yi et al., 2011). Conversely, Wnt3a treatment rescues self-renewal in ESCs inhibited by Tcf7l1 overexpression (Yi et al., 2011). Roles for Tcf7l1 in differentiation have been suggested, but in vitro differentiation assays have revealed only minor and variable lineage specification defects in Tcf7l1-deficient ESCs (Pereira et al., 2006 Salomonis et al., 2010 Tam et al., 2008). Thus, whereas the embryonic function of factors that stimulate the GRN (i.e. Oct4, Nanog and Sox2) is clearly necessary to stimulate the self-renewal of pluripotent cells as early embryos expand (Avilion et al., 2003 Mitsui et al., 2003 Nichols et al., 1998), an embryonic function for an inhibitor of GRN activity, such as Tcf7l1, has not been elucidated. As such, it is not clear why pluripotent cells express high levels of an ostensible inhibitor of their self-renewal.

With a perspective that the evolution of the pluripotency GRN in mammals included the Tcf7l1 inhibitor activity to enable some aspect of early embryogenesis, we reasoned that examining embryogenesis in Tcf7l1 mutant embryos would elucidate a role for Tcf7l1 in pluripotent cells. Building upon previous work showing that Oct4, Sox2, Nanog and Tcf7l1 are expressed during gastrulation (Avilion et al., 2003 Hart et al., 2004 Merrill et al., 2004 Morkel et al., 2003 Yamaguchi et al., 2005 Yeom et al., 1996), we define changes in their protein expression that occur in epiblast cells prior to and during cell lineage specification. Gene expression defects in Tcf7l1 -/- embryos coincided with a delay in the specification of mesoderm at the primitive streak region, demonstrating that Tcf7l1 is necessary to couple lineage specification with primitive streak morphogenesis. In vitro, ESCs required Tcf7l1 to rapidly convert to a state in which they formed mesoderm in response to Wnt/β-catenin signaling. We suggest that the activity of Tcf7l1 as a negative regulator of the pluripotency GRN is closely related to its first embryonic function, which enables appropriate responses to lineage specification signals.


Gradients and Tissue Patterning

Sophie M. Morgani , Anna-Katerina Hadjantonakis , in Current Topics in Developmental Biology , 2020

2 Signaling interactions during gastrulation

Gastrulation is driven by embryonic and extraembryonic signaling centers, sources of ligands or inhibitors that exert spatial and temporal control over signaling activity. Little is known about how signaling factors travel within the mammalian embryo but experiments in other organisms suggest that WNT, BMP, Nodal and FGF act as morphogens, diffusing from their source to establish concentration gradients that direct cell fate.

At the onset of gastrulation, localized ligand production and complex signaling pathway interactions establish a signaling hub within the proximal posterior epiblast ( Fig. 2 A ). Initially, uncleaved pro-NODAL, produced by the epiblast, induces the expression of Bmp4 within the adjacent ExE ( Ben-Haim et al., 2006 Winnier et al., 1995 ). The ExE is also a source of other BMP ligands including Bmp8b ( Ying et al., 2000 ), 8a, 1 and 7 ( Pijuan-Sala et al., 2019 ), while the VE produces Bmp2 ( Ying & Zhao, 2001 ). Additionally, pro-NODAL induces the expression of its own convertase enzymes in the ExE ( Ben-Haim et al., 2006 ). These enzymes convert pro-NODAL it to its active NODAL form in the adjacent proximal epiblast, which then augments its own expression through an autoregulatory loop ( Norris et al., 2002 Saijoh et al., 2000 ). Wnt3 is expressed by posterior VE cells overlying the site of prospective PS formation ( Rivera-Perez & Magnuson, 2005 ). Wnt3 stimulates its own expression within the epiblast as well as that of Nodal ( Ben-Haim et al., 2006 Norris et al., 2002 Tortelote et al., 2013 Yoon et al., 2015 ). BMP signaling also induces Wnt3 expression ( Ben-Haim et al., 2006 Miura, Singh, & Mishina, 2010 ). Together, these interactions enhance WNT, BMP and Nodal signaling activity within the proximal posterior epiblast.

Fig. 2 . Critical signaling networks at gastrulation. Schematic diagram summarizing the complex feedback loops between WNT, BMP, Nodal and FGF signaling that regulate gastrulation. Blue arrows denote positive interactions. Pink lines denote negative interactions. Dashed lines indicate interactions that are suggested but still unclear. (A) At the onset of gastrulation, uncleaved pro-NODAL, in the epiblast, induces the expression of Bmp4 and its own convertase enzymes in the extraembryonic ectoderm (ExE). The convertase enzymes cleave pro-NODAL to active NODAL, which induces its own expression through an autoregulatory loop. Wnt3 is produced by posterior visceral endoderm (pVE) cells at the embryonic-extraembryonic border. Wnt3 stimulates its own expression as well as that of Nodal. BMP signaling also induces Wnt3 expression. In addition, signaling is confined to the posterior by inhibitors secreted from the anterior visceral endoderm (AVE). CERL1 and LEFTY1 inhibit BMP and Nodal and DKK1 inhibits WNT signaling. FGF ligands are also expressed within the proximal posterior region and throughout the PS. While FGF is critical for gastrulation, there is less information on its interactions with this signaling network. However, genetic experiments suggest that it may be upstream of WNT signaling. Additionally, although FGF signaling activity is restricted to the posterior of the embryo, it is unclear whether there are inhibitors expressed within the anterior that mediate this restriction. Therefore, the proximal posterior epiblast exhibits high WNT, BMP, Nodal and FGF activity. The combination of these signals stimulates epiblast cells to undergo an epithelial-mesenchymal transition (EMT) in order to exit the epiblast through the primitive streak (PS). (B) As gastrulation proceeds, the embryo grows in size, the PS extends distally and new cell types arise. Cells within the PS express WNT3, WNT3A, FGF4, FGF8 and NODAL ligands. Cells that traverse the posterior PS (pPS) express LEFTY2, a NODAL antagonist. Furthermore, in vitro data suggests that Nodal and BMP signaling pathways inhibit one another. Thus, NODAL activity is restricted posteriorly. As BMP4 is expressed proximally, by the ExE and extraembryonic mesoderm (ExM), the expansion of the embryo moves the distal cells further from the source of BMP. Additionally, cells within the anterior PS (aPS) secrete CHORDIN, NOGGIN and DKK1 restricting BMP and WNT signaling distally. Therefore, the proximal posterior of the embryo (pPS) is high in BMP and low in Nodal signaling activity, an environment that promotes embryonic mesoderm (Mes) and extraembryonic mesoderm (ExM) fates. Conversely, the distal embryo (aPS) is low in BMP and high in Nodal signaling activity, promoting definitive endoderm (DE) and axial mesoderm (AxM) fates. The expression of WNT inhibitors in the aPS suggests that there may also be a proximal-distal WNT gradient although this has not been carefully characterized. Similarly, it is unclear whether there is a gradient of FGF signaling activity across the PS. During these later gastrulation stages, the interactions in panel A likely remain however, we removed these details from this panel for simplicity. pPS, posterior PS Pr, proximal Ds, distal A, anterior P, posterior.

Mechanisms are also in place to actively confine WNT, BMP and Nodal signaling responses to the posterior of the embryo, namely the expression of inhibitors by the anterior visceral endoderm (AVE), a signaling center overlying the anterior epiblast. Secreted CER1 and LEFTY1 inhibit BMP and Nodal signaling while DKK1 inhibits WNT activity ( Belo et al., 1997 Meno et al., 1996 Glinka et al., 1998 Kawano & Kypta, 2003 Kemp et al., 2005 ) within the anterior epiblast. While FGF is critical for gastrulation, it is less clear how it interacts with the other signaling pathways and how its expression is restricted to the posterior of the embryo.

During gastrulation, the embryo substantially changes size and shape. These extensive morphological transformations shift the position of cells and signals such that the signaling landscape of the embryo is continuously evolving. As development proceeds, the PS extends distally, as does the expression domain of Wnt3, Wnt3a ( Kemp et al., 2005 Liu et al., 1999 Takada et al., 1994 ) and Nodal ( Norris & Robertson, 1999 ) ligands ( Fig. 2 B). However, Bmp4 is expressed only within the ExE. Therefore, cells traversing the PS at later time points within the distal region of the embryo are furthest from the source of BMP4 and show reduced signaling activity compared to cells within the proximal region of the embryo ( Morgani et al., 2018a ). Additionally, BMP and Nodal signaling pathways cross inhibit one another, hence the extension of the PS relieves Nodal inhibition by BMP resulting in elevated Nodal signaling within the anterior PS ( Chhabra et al., 2019 Heemskerk et al., 2019 Senft et al., 2019 ). Cells that have traversed the PS also express signaling inhibitors, which reinforce discrete proximal and distal signaling environments that promote different cell fates. The nascent mesoderm cells within the proximal, posterior PS express Lefty2 ( Meno et al., 1997 Peng et al., 2019 ), a Nodal pathway inhibitor, while cells at the anterior PS express the WNT antagonist Dkk1 and the BMP antagonists Chordin and Noggin ( Klingensmith et al., 1999 McMahon et al., 1998 Pijuan-Sala et al., 2019 ). Thus, BMP signaling activity is high proximally and Nodal signaling is high distally. These observations also suggest that WNT signaling may be higher in the posterior compared to anterior PS, although this has not been clearly demonstrated. It is also unknown whether there is an FGF signaling gradient across the PS.

While we know what cells express signaling pathway components, it is not always clear which cells respond to these signals. This will be discussed in subsequent sections.



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