The primitive streak is a structure that forms in the early

embryo An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...

amniote Amniotes are a clade of tetrapod vertebrates that comprises sauropsids (including all reptiles and birds, and extinct parareptiles and non-avian dinosaurs) and synapsids (including pelycosaurs and therapsids such as mammals). They are disti ...

s. In

amphibian Amphibians are tetrapod, four-limbed and ectothermic vertebrates of the Class (biology), class Amphibia. All living amphibians belong to the group Lissamphibia. They inhabit a wide variety of habitats, with most species living within terres ...

s the equivalent structure is the

blastopore Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of cells), or in mammals the blastocyst is reorganized into a multilayered structure known as the gastrula. Be ...

. During early

embryonic development An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...

, the embryonic disc becomes oval shaped, and then pear-shaped with the broad end towards the anterior, and the narrower region projected to the posterior. The primitive streak forms a longitudinal midline structure in the narrower posterior (caudal) region of the developing embryo on its dorsal side. At first formation the primitive streak extends for half the length of the embryo. In the human embryo this appears by stage 6, about 17 days. The primitive streak establishes

bilateral symmetry Symmetry in biology refers to the symmetry observed in organisms, including plants, animals, fungi, and bacteria. External symmetry can be easily seen by just looking at an organism. For example, take the face of a human being which has a pla ...

, determines the site of gastrulation, and initiates

germ layer A germ layer is a primary layer of cells that forms during embryonic development. The three germ layers in vertebrates are particularly pronounced; however, all eumetazoans (animals that are sister taxa to the sponges) produce two or three pr ...

formation. To form the primitive streak

mesenchymal stem cell Mesenchymal stem cells (MSCs) also known as mesenchymal stromal cells or medicinal signaling cells are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage c ...

s are arranged along the prospective midline, establishing the second embryonic axis, and the site 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 left–right and cranial–caudal body axes. Gastrulation involves the ingression of

mesoderm The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical E ...

progenitors and their migration to their ultimate position, where they will differentiate into the mesoderm germ layer that, together with endoderm and ectoderm germ layers, will give rise to all the tissues of the adult organism.

Structure

The

epiblast In amniote embryonic development, the epiblast (also known as the primitive ectoderm) is one of two distinct cell layers arising from the inner cell mass in the mammalian blastocyst, or from the blastula in reptiles and birds, the other layer is t ...

, a single

epithelial layer Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

of the bilaminar embryonic disc, is the source of all embryonic material in

s, and some of its cells will give rise to the primitive streak. In

s the equivalent structure is the

. The primitive streak forms a longitudinal midline structure in the narrower caudal (posterior) region of the developing embryo on its dorsal side. At first formation the primitive streak extends for half the length of the embryo. In the human embryo this appears by Carnegie stage 6, about 17 days. Towards the cranial (anterior) end of the disc the primitive streak expands into an area known as the

primitive node The primitive node (or primitive knot) is the organizer for gastrulation in most amniote embryos. In birds it is known as Hensen's node, and in amphibians it is known as the Spemann-Mangold organizer. It is induced by the Nieuwkoop center in am ...

which is the organizer for

gastrulation Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of cells), or in mammals the blastocyst is reorganized into a multilayered structure known as the gastrula. Be ...

. In birds including the chick this organizing node is called

Hensen's node The primitive node (or primitive knot) is the organizer for gastrulation in most amniote embryos. In birds it is known as Hensen's node, and in amphibians it is known as the Spemann-Mangold organizer. It is induced by the Nieuwkoop center i ...

. In

s where it was first identified, it is known as the

Spemann-Mangold organizer The Spemann-Mangold organizer is a group of cells that are responsible for the induction of the neural tissues during development in amphibian embryos. First described in 1924 by Hans Spemann and Hilde Mangold, the introduction of the organizer prov ...

. In the middle of the node is a circular depression termed the primitive pit. The primitive pit extends towards the caudal end in a narrow depression in the primitive streak called the primitive groove. The groove is created by infolding of epiblastic cells. Following its appearance and formation of the node, pit, and groove, the streak starts to regress caudally. Around day 20 in the human embryo, the remaining parts of the streak enlarge to produce a midline caudal cell mass termed the ''tail bud'' or ''caudal eminence''. Also at that time the

notochord In anatomy, the notochord is a flexible rod which is similar in structure to the stiffer cartilage. If a species has a notochord at any stage of its life cycle (along with 4 other features), it is, by definition, a chordate. The notochord consis ...

develops cranially from the primitive node. By day 22 the primitive streak has regressed to between 10 and 20% of the embryo's length, and by day 26 has seemingly disappeared. Gray14

Formation

The chick

as a

model organism A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workin ...

has provided much information about the formation of the primitive streak. In the chick

blastula Blastulation is the stage in early animal embryonic development that produces the blastula. In mammalian development the blastula develops into the blastocyst with a differentiated inner cell mass and an outer trophectoderm. The blastula (from ...

its formation involves the coordinated movement and re-arrangement of cells in the epiblast. 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 vortex movements likened to polonaise movement is key for the formation of the primitive streak. Cells overlaying

Koller's sickle In avian gastrulation, Koller's sickle is a local thickening of cells at the posterior edge of the upper layer of the area pellucida called the epiblast. Koller's sickle is crucial for avian development, due to its critical role in inducing the di ...

in the posterior end of the chick 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 active proliferation, oriented

cell division Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...

, cell-cell intercalation and

chemotactic Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemical ...

cell movement, have been proposed to explain the nature of the cellular movements required to form the primitive streak. 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. 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 In amniote embryology, the hypoblast, is one of two distinct layers arising from the inner cell mass in the mammalian blastocyst, or from the blastodisc in reptiles and birds. The hypoblast gives rise to the yolk sac, which in turn gives rise to ...

, where the extraembryonic 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 and other mammals this structure is known as the

anterior visceral endoderm In amniote embryology, the hypoblast, is one of two distinct layers arising from the inner cell mass in the mammalian blastocyst, or from the blastodisc in reptiles and birds. The hypoblast gives rise to the yolk sac, which in turn gives rise to ...

(AVE). The AVE migrates from the visceral endoderm (hypoblast). The hypoblast also plays an important role 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.

Signaling pathways

The formation of the primitive streak in the chick, is highly regulated by a complex network of

signaling pathways Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...

. Activation of various secreted factors (Vg1,

Nodal Nodal homolog is a secretory protein that in humans is encoded by the ''NODAL'' gene which is located on chromosome 10q22.1. It belongs to the transforming growth factor beta superfamily (TGF-β superfamily). Like many other members of this superf ...

, Wnt8C,

FGF8 Fibroblast growth factor 8 (FGF-8) is a protein that in humans is encoded by the ''FGF8'' gene. Function The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and ...

and

Chordin Chordin (from Greek χορδή, string, catgut) is a protein with a prominent role in dorsal–ventral patterning during early embryonic development. In humans it is encoded for by the ''CHRD'' gene. History Chordin was originally identified ...

) and

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

s (

Brachyury T-box transcription factor T, also known as Brachyury protein, is encoded for in humans by the ''TBXT'' gene. Brachyury functions as a transcription factor within the T-box family of genes. Brachyury homologs have been found in all bilaterian a ...

and

Goosecoid Homeobox protein goosecoid (GSC) is a homeobox protein that is encoded in humans by the ''GSC'' gene. Like other homeobox proteins, goosecoid functions as a transcription factor involved in morphogenesis. In ''Xenopus'', ''GSC'' is thought to pla ...

) adjacent to the site of streak formation is required for this process.

Vg1 and Wnt signaling

Similarly, Vg1 (a

transforming growth factor beta family The transforming growth factor beta (TGF-β) superfamily is a large group of structurally related cell regulatory proteins that was named after its first member, TGF-β1, originally described in 1983. They interact with TGF-beta receptors. Ma ...

member (TGF-β)) 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-catenin Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcripti ...

mutant embryos. In addition, mutating the intracellular negative regulator of Wnt signaling,

Axin Axin-1 is a protein that in humans is encoded by the ''AXIN1'' gene. Function This gene encodes a cytoplasmic protein which contains a regulation of G-protein signaling (RGS) domain and a dishevelled and axin (DIX) domain. The encoded protei ...

, 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 (LEF1) is a protein that in humans is encoded by the ''LEF1'' gene. It's a member of T cell factor/lymphoid enhancer factor ( TCF/LEF) family. Function Lymphoid enhancer-binding factor-1 (LEF1) is a 48-kD nu ...

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.

Nodal signaling

, a known mesodermal inducer of the

(TGFB family), 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 In Greek mythology, Cerberus (; grc-gre, Κέρβερος ''Kérberos'' ), often referred to as the hound of Hades, is a multi-headed dog that guards the gates of the Underworld to prevent the dead from leaving. He was the offspring of the mo ...

(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.

FGF signaling

Another important pathway in modulating formation of the primitive streak is FGF, 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.

BMP signaling

Finally, BMP 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

bioethics Bioethics is both a field of study and professional practice, interested in ethical issues related to health (primarily focused on the human, but also increasingly includes animal ethics), including those emerging from advances in biology, med ...

, where some experts have argued that experimentation with human embryos is permissible, but 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. In some countries, it is illegal to develop a human embryo for more than 14 days outside a woman's body.

Additional images

File:Gray17.png, Human embryo—length, 2 mm. Dorsal view, with the amnion laid open. X 30. File:Gray21.png, Lateral section through the mammalian blastodisc.

References

{{Embryology Animal developmental biology