Primitive streak
Encyclopedia
The primitive streak is a structure that forms during the early stages of avian
, reptilian
and mammalian embryonic development.
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 (endoderm
, mesoderm
, ectoderm
) that will give rise to all the tissues
of the adult organism.
embryo can be easily manipulated, most of our knowledge about the primitive streak comes from avian studies. The marginal zone
of a chick embryo contains cells
that will contribute to the streak . This region has a defined anterior to posterior gradient in its ability to induce the primitive streak, with the posterior end having the highest potential .
The epiblast
, a single epithelial layer
blastodisc, is the source of all embryonic material in amniote
s and some of its cells will give rise to the primitive streak . All cells in the epiblast can respond to signals from the marginal zone , but once a given region is induced by these signals and undergoes streak formation, the remaining cells in the epiblast are no longer responsive to these inductive signals and prevent the formation of another streak .
Underlying the epiblast, is the hypoblast
, where the extra-embryonic tissue originates . In the chick, the absence of the hypoblast results in multiple streaks , suggesting that its presence is important for regulating the formation of a single primitive streak. In mice, this structure is known as the Anterior Visceral Endoderm (AVE) .
in the posterior end of the embryo move towards the midline, meet and change direction towards the center of the epiblast. Cells from the lateral posterior marginal zone replace those cells that left Koller’s Sickle by meeting at the center of this region, changing direction and extending anteriorly . As these cells move and concentrate at the posterior end of the embryo, the streak undergoes a single- to multi-layered epithelial sheet transition that makes it a macroscopically visible structure . Several mechanisms, including oriented cell division
, cell-cell intercalation and chemotactic
cell movement , have been proposed to explain the nature of the cellular movements required to form the primitive streak.
that work together to ensure that this process is highly-regulated. Activation of various secreted factors (Vg1, Nodal
, Wnt8C
, FGF8
and Chordin
) and transcription factor
s (Brachyury
and Goosecoid
) adjacent to the site of streak formation is required for this process .
In addition, structures, such as the hypoblast, also play an important in the regulation of streak formation. Removal of the hypoblast in the chick results in correctly patterned ectopic
streaks, suggesting that the hypoblast serves to inhibit formation of the primitive streak .
mutant embryos . In addition, mutating the intracellular negative regulator of Wnt signaling, Axin
, and misexpression of the chick cWnt8C produces multiple streaks in mouse embryos. Localization of Wnt and components of its pathway, Lef1
and B-catenin, further supports streak-inducing role in the marginal zone . Furthermore, it is expressed as a gradient decreasing from posterior to anterior , corresponding to the streak-inducing ability of the marginal zone. Misexpression of Vg1 or Wnt1 alone failed to induce an ectopic streak in the chick, but together their misexpression resulted in ectopic streak formation, confirming that the streak-inducing ability of the posterior marginal zone could be attributed to Wnt signaling and that Vg1 and Wnt must cooperate to induce this process. Misexpression of Vg1 along with Wnt antagonists, Crescent or Dkk-1
, prevents the formation of ectopic streaks , demonstrating the importance of Wnt activity in the formation of Vg1-induced ectopic streaks and hence its implication in normal primitive streak formation.
is able to generate a complete axis until the time of gastrulation and primitive streak formation . This ability to generate a streak from the pre-streak stage chick embryo indicates that there must be a mechanism to ensure that only a single streak forms. The hypoblast secretes an antagonist of Nodal that prevents ectopic streak formation in the chick .
, a known mesodermal inducer of the TGFB superfamily , has been implicated in streak formation. Mouse embryos mutant for Nodal fail to gastrulate and lack most mesoderm , but more than playing a role in mesoderm induction, Nodal regulates the induction and/or maintenance of the primitive streak .In the presence of hypoblast, Nodal is unable to induce ectopic streaks in the chick embryo, while its removal, induces expression of Nodal, Chordin and Brachyury , suggesting that the hypoblast must have a certain inhibitory effect on Nodal signaling. Indeed, the multifunctional antagonist of Nodal, Wnt and BMP signaling, Cerberus (produced in the hypoblast) and Cerberus-Short (which inhibits only Nodal), through its effect on Nodal signaling, inhibits streak formation . Eventually, the hypoblast gets displaced anteriorly by the moving endoblast, allowing streak formation at the posterior end. At the anterior end, the presence of the hypoblast and the antagonists it secretes, such as Cerberus, inhibit the expression of Nodal and hence restrict streak formation to the posterior end only . Similarly to the hypoblast in chick, the AVE in the mouse secretes two antagonists of Nodal signaling, Cerberus-like, Cerl, and Lefty1
. In mouse, Cer-/-; Lefty1-/- double mutants develop multiple streaks as indicated by ectopic expression of Brachyury and can be partially rescued by the removal of one copy of the Nodal gene . In the mouse, the AVE restricts streak formation through the redundant functions of Cer1 and Lefty1, which negatively regulate Nodal signaling . The role of the mouse’s AVE in ensuring the formation of a single primitive streak is evolutionarily conserved in the hypoblast of the chick .
, which is thought to work together with Nodal to regulate this process . Inhibition of FGF signaling through expression of a dominant negative receptor, using a FGF receptor inhibitor (SU5402) or depletion of FGF ligands, inhibit mesoderm formation
and this in turn, inhibits streak formation . Furthermore, ectopic streak formation induced by Vg1 required FGF signaling .
signaling is also important for regulating the process of streak formation in the chick embryo. The site of streak formation is characterized by low BMP signals , while the rest of the epiblast displays high levels of BMP activation . In addition, misexpression of either BMP4 or BMP7 prevents streak formation, while the BMP inhibitor Chordin induces ectopic streak formation in the chick , suggesting that streak formation is likely to require BMP inhibition.
, where some experts have argued that experimentation with human embryos is permissible only before the primitive streak develops, generally around the fourteenth day of existence. The development of the primitive streak is taken, by such bioethicists, to signify the creation of a unique, human being.
Bird
Birds are feathered, winged, bipedal, endothermic , egg-laying, vertebrate animals. Around 10,000 living species and 188 families makes them the most speciose class of tetrapod vertebrates. They inhabit ecosystems across the globe, from the Arctic to the Antarctic. Extant birds range in size from...
, reptilian
Reptile
Reptiles are members of a class of air-breathing, ectothermic vertebrates which are characterized by laying shelled eggs , and having skin covered in scales and/or scutes. They are tetrapods, either having four limbs or being descended from four-limbed ancestors...
and mammalian embryonic development.
Introduction
During the early stages of development, the primitive streak is the structure that will establish bilateral symmetry, determine the site of gastrulationGastrulation
Gastrulation is a phase early in the embryonic development of most animals, during which the single-layered blastula is reorganized into a trilaminar structure known as the gastrula. These three germ layers are known as the ectoderm, mesoderm, and endoderm.Gastrulation takes place after cleavage...
and initiate germ layer
Germ layer
A germ layer, occasionally referred to as a germinal epithelium, is a group of cells, formed during animal embryogenesis. Germ layers are particularly pronounced in the vertebrates; however, all animals more complex than sponges produce two or three primary tissue layers...
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
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
, 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 (endoderm
Endoderm
Endoderm is one of the three primary germ cell layers in the very early embryo. The other two layers are the ectoderm and mesoderm , with the endoderm as the intermost layer...
, mesoderm
Mesoderm
In all bilaterian animals, the mesoderm is one of the three primary germ cell layers in the very early embryo. The other two layers are the ectoderm and endoderm , with the mesoderm as the middle layer between them.The mesoderm forms mesenchyme , mesothelium, non-epithelial blood corpuscles and...
, ectoderm
Ectoderm
The "ectoderm" is one of the three primary germ cell layers in the very early embryo. The other two layers are the mesoderm and endoderm , with the ectoderm as the most exterior layer...
) that will give rise to all the tissues
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
of the adult organism.
Components
Given that the chickChicken
The chicken is a domesticated fowl, a subspecies of the Red Junglefowl. As one of the most common and widespread domestic animals, and with a population of more than 24 billion in 2003, there are more chickens in the world than any other species of bird...
embryo can be easily manipulated, most of our knowledge about the primitive streak comes from avian studies. The marginal zone
Marginal zone
The marginal zone is the region at the interface between the non-lymphoid red pulp and the lymphoid white-pulp of the spleen. A marginal zone also exists in lymph nodes.-Composition and markers:It is composed of cells derived...
of a chick embryo contains cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
that will contribute to the streak . This region has a defined anterior to posterior gradient in its ability to induce the primitive streak, with the posterior end having the highest potential .
The epiblast
Epiblast
In amniote animal embryology, the epiblast is a tissue type derived either from the inner cell mass in mammals or the blastodisc in birds and reptiles. It lies above the hypoblast.-Mammals:...
, a single epithelial layer
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
blastodisc, is the source of all embryonic material in amniote
Amniote
The amniotes are a group of tetrapods that have a terrestrially adapted egg. They include synapsids and sauropsids , as well as their fossil ancestors. Amniote embryos, whether laid as eggs or carried by the female, are protected and aided by several extensive membranes...
s and some of its cells will give rise to the primitive streak . All cells in the epiblast can respond to signals from the marginal zone , but once a given region is induced by these signals and undergoes streak formation, the remaining cells in the epiblast are no longer responsive to these inductive signals and prevent the formation of another streak .
Underlying the epiblast, is the hypoblast
Hypoblast
The hypoblast is a tissue type that forms from the inner cell mass. It lies beneath the epiblast and consists of small cuboidal cells.Extraembryonic endoderm is derived from hypoblast.-External links:...
, where the extra-embryonic tissue originates . In the chick, the absence of the hypoblast results in multiple streaks , suggesting that its presence is important for regulating the formation of a single primitive streak. In mice, this structure is known as the Anterior Visceral Endoderm (AVE) .
Cellular Movements
The formation of the primitive streak involves the coordinated movement and re-arrangement of cells in the epiblast. Even before the streak is visible, epiblast cells have started to move . Two counter-rotating flows of cells meet at the posterior end, where the streak forms . There is little movement in the center of these flows, while the greatest movement is observed at the periphery of the vortices . The Polonaise Movement is key for the formation of the primitive streak. Cells overlaying Koller’s SickleKoller's sickle
In avian gastrulation, Koller's sickle is a local thickening of cells that acts as a margin separating sheets of cells from posterior margin of avian blastoderms from hypoblasts as they migrate anteriorly to push primary hypoblast cells anteriorly to form a secondary hypoblast known as the...
in the posterior end of the embryo move towards the midline, meet and change direction towards the center of the epiblast. Cells from the lateral posterior marginal zone replace those cells that left Koller’s Sickle by meeting at the center of this region, changing direction and extending anteriorly . As these cells move and concentrate at the posterior end of the embryo, the streak undergoes a single- to multi-layered epithelial sheet transition that makes it a macroscopically visible structure . Several mechanisms, including oriented cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
, cell-cell intercalation and chemotactic
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...
cell movement , have been proposed to explain the nature of the cellular movements required to form the primitive streak.
Formation
The formation of the primitive streak relies on a complex network of signaling pathwaysSignal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
that work together to ensure that this process is highly-regulated. Activation of various secreted factors (Vg1, Nodal
NODAL
Nodal is a protein that in humans is encoded by the NODAL gene. It is a member of the TGF beta superfamily. Like many other members of this superfamily, it is involved in cell differentiation...
, Wnt8C
Wnt signaling pathway
The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...
, FGF8
FGF8
Fibroblast growth factor 8 is a protein that in humans is encoded by the FGF8 gene.-External links:*...
and Chordin
Chordin
Chordin is a polypeptide that dorsalizes the developing embryo by binding ventralizing TGFβ proteins such as bone morphogenetic proteins. It may also play a role in organogenesis. There are five named isoforms of this protein that are produced by alternative splicing.In humans, the chordin peptide...
) and transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
s (Brachyury
Brachyury
Brachyury is a protein that in humans is encoded by the T gene. Brachyury is a transcription factor within the T-box complex of genes. It has been found in all bilaterian animals that have been screened, and is also present in the cnidaria.-History:...
and Goosecoid
GSC (gene)
Homeobox protein goosecoid is a protein that in humans is encoded by the GSC gene.-Further reading:-External links:*...
) adjacent to the site of streak formation is required for this process .
In addition, structures, such as the hypoblast, also play an important in the regulation of streak formation. Removal of the hypoblast in the chick results in correctly patterned ectopic
Ectopic expression
Ectopic expression is the expression of a gene in an abnormal place in an organism. This can be caused by a disease, or it can be artificially produced as a way to help determine what the function of that gene is....
streaks, suggesting that the hypoblast serves to inhibit formation of the primitive streak .
Vg1 and Wnt Signaling
Similarly, Vg1 (a TGFB family member) misexpression and grafts of the posterior marginal zone in chicks can also induce ectopic streaks, but only within the marginal zone of the embryo , indicating a specific characteristic of this region in its ability to induce streak formation. Several lines of evidence point to Wnt expression as the determinant of this ability. Deletion of Wnt3 in mouse embryos results in the absence of a streak formation, similarly to the phenotype of B-cateninBeta-catenin
Beta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
mutant embryos . In addition, mutating the intracellular negative regulator of Wnt signaling, Axin
Wnt signaling pathway
The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...
, and misexpression of the chick cWnt8C produces multiple streaks in mouse embryos. Localization of Wnt and components of its pathway, Lef1
Lymphoid enhancer-binding factor 1
Lymphoid enhancer-binding factor 1 is a protein that in humans is encoded by the LEF1 gene.- Function :Lymphoid enhancer-binding factor-1 is a 48-kD nuclear protein that is expressed in pre-B and T cells. It binds to a functionally important site in the T-cell receptor-alpha enhancer and confers...
and B-catenin, further supports streak-inducing role in the marginal zone . Furthermore, it is expressed as a gradient decreasing from posterior to anterior , corresponding to the streak-inducing ability of the marginal zone. Misexpression of Vg1 or Wnt1 alone failed to induce an ectopic streak in the chick, but together their misexpression resulted in ectopic streak formation, confirming that the streak-inducing ability of the posterior marginal zone could be attributed to Wnt signaling and that Vg1 and Wnt must cooperate to induce this process. Misexpression of Vg1 along with Wnt antagonists, Crescent or Dkk-1
DKK1
Dickkopf-related protein 1 is a protein that in humans is encoded by the DKK1 gene.-Further reading:...
, prevents the formation of ectopic streaks , demonstrating the importance of Wnt activity in the formation of Vg1-induced ectopic streaks and hence its implication in normal primitive streak formation.
Hypoblast
Any given slice from the blastodermBlastoderm
-In amniotes:A blastoderm is the layer of cells formed at one pole of macrolecithal eggs such as the yolky egg of birds. The yolk prevents the division from taking place through the egg, resulting in meroblastic cleavage during the many cleavage divisions...
is able to generate a complete axis until the time of gastrulation and primitive streak formation . This ability to generate a streak from the pre-streak stage chick embryo indicates that there must be a mechanism to ensure that only a single streak forms. The hypoblast secretes an antagonist of Nodal that prevents ectopic streak formation in the chick .
Nodal Signaling
NodalNODAL
Nodal is a protein that in humans is encoded by the NODAL gene. It is a member of the TGF beta superfamily. Like many other members of this superfamily, it is involved in cell differentiation...
, a known mesodermal inducer of the TGFB superfamily , has been implicated in streak formation. Mouse embryos mutant for Nodal fail to gastrulate and lack most mesoderm , but more than playing a role in mesoderm induction, Nodal regulates the induction and/or maintenance of the primitive streak .In the presence of hypoblast, Nodal is unable to induce ectopic streaks in the chick embryo, while its removal, induces expression of Nodal, Chordin and Brachyury , suggesting that the hypoblast must have a certain inhibitory effect on Nodal signaling. Indeed, the multifunctional antagonist of Nodal, Wnt and BMP signaling, Cerberus (produced in the hypoblast) and Cerberus-Short (which inhibits only Nodal), through its effect on Nodal signaling, inhibits streak formation . Eventually, the hypoblast gets displaced anteriorly by the moving endoblast, allowing streak formation at the posterior end. At the anterior end, the presence of the hypoblast and the antagonists it secretes, such as Cerberus, inhibit the expression of Nodal and hence restrict streak formation to the posterior end only . Similarly to the hypoblast in chick, the AVE in the mouse secretes two antagonists of Nodal signaling, Cerberus-like, Cerl, and Lefty1
Lefty (protein)
Lefty are proteins that are closely related members of the TGF-beta family of growth factors. These proteins are secreted and play a role in left-right asymmetry determination of organ systems during development...
. In mouse, Cer-/-; Lefty1-/- double mutants develop multiple streaks as indicated by ectopic expression of Brachyury and can be partially rescued by the removal of one copy of the Nodal gene . In the mouse, the AVE restricts streak formation through the redundant functions of Cer1 and Lefty1, which negatively regulate Nodal signaling . The role of the mouse’s AVE in ensuring the formation of a single primitive streak is evolutionarily conserved in the hypoblast of the chick .
FGF Signaling
Another important pathway in modulating formation of the primitive streak is FGFFibroblast growth factor
Fibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal...
, which is thought to work together with Nodal to regulate this process . Inhibition of FGF signaling through expression of a dominant negative receptor, using a FGF receptor inhibitor (SU5402) or depletion of FGF ligands, inhibit mesoderm formation
FGF and Mesoderm Formation
Role of FGF Signaling in Mesoderm FormationMesoderm formation is a complex developmental process involving an intricate network of signaling pathways that coordinate their activities to ensure that a selective group of cells will eventually give rise to mesodermal tissues in the adult organism...
and this in turn, inhibits streak formation . Furthermore, ectopic streak formation induced by Vg1 required FGF signaling .
BMP Signaling
Finally, BMPBone morphogenetic protein
Bone morphogenetic proteins are a group of growth factors also known as cytokines and as metabologens . Originally discovered by their ability to induce the formation of bone and cartilage, BMPs are now considered to constitute a group of pivotal morphogenetic signals, orchestrating tissue...
signaling is also important for regulating the process of streak formation in the chick embryo. The site of streak formation is characterized by low BMP signals , while the rest of the epiblast displays high levels of BMP activation . In addition, misexpression of either BMP4 or BMP7 prevents streak formation, while the BMP inhibitor Chordin induces ectopic streak formation in the chick , suggesting that streak formation is likely to require BMP inhibition.
Ethical implications
The primitive streak is an important concept in bioethicsBioethics
Bioethics is the study of controversial ethics brought about by advances in biology and medicine. Bioethicists are concerned with the ethical questions that arise in the relationships among life sciences, biotechnology, medicine, politics, law, and philosophy....
, where some experts have argued that experimentation with human embryos is permissible only before the primitive streak develops, generally around the fourteenth day of existence. The development of the primitive streak is taken, by such bioethicists, to signify the creation of a unique, human being.