Editing Gastrulation

{{Short description|Embryologic stage in which germ layers form}}
{{Infobox embryology
| Name     = Gastrulation
| Latin    =
| Image    = Blastula.png
| Caption  = Gastrulation occurs when a [[blastula]], made up of one layer, folds inward and enlarges to create a gastrula. This diagram is color-coded: [[ectoderm]], blue; [[endoderm]], green; [[blastocoel]] (the yolk sac), yellow; and [[archenteron]] (the primary gut), purple.
| Image2   =
| Caption2 =
}}

'''Gastrulation''' is the stage in the early [[embryonic development]] of most [[animals]], during which the [[blastula]] (a single-layered hollow sphere of [[Cell (biology)|cell]]s), or in mammals, the [[blastocyst]], is reorganized into a two-layered or three-layered embryo known as the '''gastrula'''.<ref>{{Cite book |last=Urry |first=Lisa |title=Campbell Biology |publisher=Pearson |year=2016 |isbn=978-0134093413 |edition=11th |pages=1047}}</ref> Before gastrulation, the [[embryo]] is a continuous [[Epithelium|epithelial]] sheet of cells; by the end of gastrulation, the embryo has begun [[Cellular differentiation|differentiation]] to establish distinct [[cell lineage]]s, set up the basic axes of the body (e.g. [[Anatomical terms of location#Dorsal and ventral|dorsal–ventral]], [[Anatomical terms of location#Anterior and posterior|anterior–posterior]]), and internalized one or more cell types, including the prospective [[Gastrointestinal tract|gut]].<ref name="Gilbert-2016">{{Cite book|last=Gilbert|first=Scott F. |title=Developmental biology|date=2016|author2=Michael J. F. Barresi|isbn=978-1-60535-470-5|edition=Eleventh |location=Sunderland, Massachusetts |publisher=Sinauer |oclc=945169933}}</ref>

== Gastrula layers ==
[[File:Gastrulation in 3D.ogg|thumb|A description of the gastrulation process in a human embryo in three dimensions]]
In [[Triploblasty|triploblastic]] organisms, the gastrula is trilaminar (three-layered). These three [[germ layers]] are the [[ectoderm]] (outer layer), [[mesoderm]] (middle layer), and [[endoderm]] (inner layer).<ref name=mundlos2009>Mundlos 2009: [https://books.google.com/books?id=FlfPSpBvKLgC&pg=PA422 p. 422]</ref><ref name="mcgeady-2004-p.34">McGeady, 2004: p. 34</ref> In [[Diploblasty|diploblastic]] organisms, such as [[Cnidaria]] and [[Ctenophora]], the gastrula has only ectoderm and endoderm. The two layers are also sometimes referred to as the ''hypoblast'' and ''epiblast''.<ref>{{Cite book|title=Essential Developmental Biology|last=Jonathon M.W.|first=Slack|publisher=Wiley-Blackwell|year=2013|isbn=978-0-470-92351-1|location=West Sussex, UK|page=122}}</ref> [[Sponges]] do not go through the gastrula stage.

Gastrulation takes place after [[cleavage (embryo)|cleavage]] and the formation of the blastula, or blastocyst. Gastrulation is followed by [[organogenesis]], when individual [[Organ (anatomy)|organ]]s develop within the newly formed germ layers.<ref>Hall, 1998: [https://books.google.com/books?id=JhSwumfgTQ4C&pg=PA132 pp. 132-134]</ref> Each layer gives rise to specific [[tissue (biology)|tissues]] and organs in the developing embryo.
* The ectoderm gives rise to [[Epidermis (zoology)|epidermis]], the [[nervous system]], and to the [[neural crest]] in vertebrates.<ref name="Gilbert-2016" />
* The endoderm gives rise to the [[epithelium]] of the [[Digestion|digestive system]] and [[respiratory system]], and organs associated with the digestive system, such as the [[liver]] and [[pancreas]].<ref name="Gilbert-2016" />
* The [[mesoderm]] gives rise to many cell types such as [[muscle]], [[bone]], and [[connective tissue]]. In vertebrates, mesoderm derivatives include the [[notochord]], the [[heart]], [[blood]] and [[blood vessels]], the [[cartilage]] of the [[ribs]] and [[vertebrae]], and the [[dermis]].<ref name="Gilbert-2016" /><ref name=Arnold>Arnold & Robinson, 2009</ref>
Following gastrulation, cells in the body are either organized into sheets of connected cells (as in [[epithelia]]), or as a mesh of isolated cells, such as [[mesenchyme]].<ref name="mcgeady-2004-p.34" /><ref>Hall, 1998: [https://books.google.com/books?id=JhSwumfgTQ4C&pg=PA177 p. 177]</ref>

== Basic cell movements ==
Although gastrulation patterns exhibit enormous variation throughout the animal kingdom, they are unified by the five basic types of cell movements that occur during gastrulation:<ref name="Gilbert-2016" /><ref name="Gilbert2">{{cite web |last1=Gilbert |first1=Scott F. |title=Figure 8.6, [Types of cell movements during...]. |url=https://www.ncbi.nlm.nih.gov/books/NBK9992/figure/A1689/?report=objectonly |website=www.ncbi.nlm.nih.gov |access-date=11 May 2022 |language=en |date=2000}}</ref> 
# [[Invagination]]
# [[Involution (medicine)|Involution]]
# [[Ingression (biology)|Ingression]]
# Delamination
# [[Epiboly]]

== Etymology ==
The terms "gastrula" and "gastrulation" were coined by [[Ernst Haeckel]], in his 1872 work ''"Biology of Calcareous Sponges"''.<ref>Ereskovsky 2010: [https://books.google.com/books?id=PHztG3LEUnsC&pg=PA236 p. 236]</ref>
Gastrula (literally, "little belly") is a neo-Latin diminutive based on the Ancient Greek {{lang|grc|γαστήρ}} ''{{transliteration|grc|gastḗr}}'' ("a belly").

== Importance ==
[[Lewis Wolpert]], pioneering developmental biologist in the field, has been credited for noting that "It is not birth, marriage, or death, but gastrulation which is truly the most important time in your life."<ref name="Gilbert-2016" /><ref>[[Lewis Wolpert|Wolpert L]] (2008) [https://books.google.com/books?id=VfdFOKz3O5UC&dq=%22The+triumph+of+the+embryo%22+%22It+is+not+birth%2C+marriage%2C+or+death%2C+but+gastrulation%22&pg=PA12 ''The triumph of the embryo'']. Courier Corporation, page 12. {{ISBN|978-0-486-46929-4}}</ref>

==Model systems==

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

==Protostomes versus deuterostomes==
[[File:Protovsdeuterostomes.svg|thumb|upright=1.2]]
The [[Embryological origins of the mouth and anus|distinction between]] [[protostome]]s and [[deuterostome]]s is based on the direction in which the mouth (stoma) develops in relation to the '''blastopore'''. Protostome derives from the Greek word protostoma meaning "first mouth" (πρῶτος + στόμα) whereas Deuterostome's etymology is "second mouth" from the words second and mouth (δεύτερος + στόμα).{{cn|date=April 2022}}

The major distinctions between deuterostomes and protostomes are found in [[embryonic development]]:
* Mouth/anus
** In [[protostome]] development, the first opening in development, the blastopore, becomes the animal's [[mouth]].
** In [[deuterostome]] development, the blastopore becomes the animal's [[anus]].
* [[Cleavage (embryo)|Cleavage]]
** [[Protostome]]s have what is known as ''[[Cleavage (embryo)|spiral cleavage]]'' which is ''determinate'', meaning that the fate of the cells is determined as they are formed.
** [[Deuterostome]]s have what is known as ''[[Cleavage (embryo)|radial cleavage]]'' that is ''indeterminate''.

==Sea urchins==
{{Further|Sea urchin#Development}}
[[Sea urchin]]s have been important [[model organism]]s in [[developmental biology]] since the 19th century.<ref>Laubichler, M.D. and Davidson, E. H. (2008). "Boveri's long experiment: sea urchin merogones and the establishment of the role of nuclear chromosomes in development". ''Developmental Biology''. 314(1):1–11. {{doi|10.1016/j.ydbio.2007.11.024}}.</ref> Their gastrulation is often considered the archetype for invertebrate deuterostomes.<ref name="gast-urchin">{{cite book |last1=McClay |first1=David R.|last2=Gross |first2=J.M. |last3=Range|first3=Ryan |last4=Peterson |first4=R.E. |last5=Bradham |first5=Cynthia |editor-last=Stern |editor-first=Claudio D. |title=Gastrulation: From Cells to Embryos |publisher=Cold Spring Harbor Laboratory Press |date=2004 |pages=123–137|chapter=Chapter 9: Sea Urchin Gastrulation |isbn=978-0-87969-707-5}}</ref> 

Sea urchins exhibit highly stereotyped cleavage patterns and cell fates. Maternally deposited [[mRNA]]s establish the organizing center of the sea urchin embryo. Canonical [[Wnt signaling pathway|Wnt]] and [[Notch signaling pathway|Delta-Notch]] signaling progressively segregate progressive endoderm and mesoderm.<ref>McClay, D. R. 2009. Cleavage and Gastrulation in Sea Urchin. eLS. {{doi|10.1002/9780470015902.a0001073.pub2}}</ref>

The first cells to internalize are the primary [[mesenchyme]] cells (PMCs), which have a [[Sea urchin skeletogenesis|skeletogenic]] fate, which ingress during the blastula stage. Gastrulation – internalization of the prospective [[endoderm]] and non-skeletogenic [[mesoderm]] – begins shortly thereafter with invagination and other cell rearrangements the [[vegetal pole]], which contribute approximately 30% to the final [[archenteron]] length. The [https://www.ncbi.nlm.nih.gov/books/NBK9987/figure/A1730/?report=objectonly gut's final length] depends on cell rearrangements within the archenteron.<ref>{{cite journal | author = Hardin J D | year = 1990 | title = Context-sensitive cell behaviors during gastrulation. | url = http://worms.zoology.wisc.edu/reprints/hardin_sem_DB_1990.pdf | journal = Semin. Dev. Biol. | volume = 1 | pages = 335–345 }}</ref>

==Amphibians==

The [[frog]] [[genus]] ''[[Xenopus]]'' has been used as a [[model organism]] for the study of gastrulation.<ref name="model">{{cite journal |last1=Blum |first1=Martin |last2=Beyer |first2=Tina |last3=Weber |first3=Thomas |last4=Vick |first4=Philipp |last5=Andre |first5=Philipp |last6=Bitzer |first6=Eva |last7=Schweickert |first7=Axel |title=Xenopus , an ideal model system to study vertebrate left-right asymmetry |journal=Developmental Dynamics |date=June 2009 |volume=238 |issue=6 |pages=1215–1225 |doi=10.1002/dvdy.21855 |pmid=19208433 |s2cid=39348233 |language=en|doi-access=free }}</ref>

===Symmetry breaking===
The sperm contributes one of the two [[Spindle apparatus|mitotic asters]] needed to complete first cleavage. The sperm can enter anywhere in the [[animal pole|animal half]] of the egg but its exact point of entry will break the egg's radial symmetry by organizing the [[cytoskeleton]]. Prior to first cleavage, the egg's cortex rotates relative to the internal [[cytoplasm]] by the coordinated action of [[microtubules]], in a process known as cortical rotation. This displacement brings maternally loaded determinants of cell fate from the equatorial cytoplasm and vegetal cortex into contact, and together these determinants set up the [[Primitive knot|organizer]]. Thus, the area on the vegetal side opposite the sperm entry point will become the organizer.<ref name = "Gilbert-AmpAxis">{{cite book |last=Gilbert |first=Scott F. |title=Developmental Biology |publisher=Sinauer Associates |date=2000|chapter=Axis Formation in Amphibians: The Phenomenon of the Organizer, The Progressive Determination of the Amphibian Axes|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK10101/#A2296}}</ref> [[Hilde Mangold]], working in the lab of [[Hans Spemann]], demonstrated that this special "organizer" of the embryo is [[Necessity and sufficiency|necessary and sufficient]] to induce gastrulation.<ref name="Gilbert">{{cite web |last1=Gilbert |first1=Scott F. |title=Figure 10.20, [Organization of a secondary axis...]. |url=https://www.ncbi.nlm.nih.gov/books/NBK10101/figure/A2302/?report=objectonly |website=www.ncbi.nlm.nih.gov |access-date=1 June 2020 |language=en |date=2000}}</ref><ref>{{cite journal | author = Spemann H., Mangold H. | year = 1924 | title = Über Induktion von Embryonanlagen durch Implantation artfremder Organisatoren | journal = Roux' Arch. F. Entw. Mech | volume = 100 | issue = 3–4| pages = 599–638 | doi=10.1007/bf02108133| s2cid = 12605303 }}</ref><ref>{{cite journal | author = De Robertis Edward | year = 2006 | title = Spemann's organizer and self-regulation in amphibian embryos | journal = Nature Reviews Molecular Cell Biology | volume = 7 | issue = 4| pages = 296–302 | doi = 10.1038/nrm1855 | pmid = 16482093 | pmc = 2464568 }}</ref>

The [[dorsal lip]] of the blastopore is the mechanical driver of gastrulation, and the first sign of invagination seen in the frog.{{cn|date=April 2022}}

===Germ layer differentiation===
Specification of endoderm depends on rearrangement of maternally deposited determinants, leading to nuclearization of [[Beta-catenin]]. Mesoderm is [[Cellular differentiation|induced]] by signaling from the presumptive endoderm to cells that would otherwise become ectoderm.<ref name="Gilbert-AmpAxis"/>

=== Cell signaling ===
In the frog, ''Xenopus,'' one of the signals is [[retinoic acid]] (RA).<ref name="Zorn A-2009">{{Cite journal|last=Zorn A|first=Wells J|date=2009|title=Vertebrate Endoderm Development and Organ Formation|journal=Annu Rev Cell Dev Biol|volume=25|pages=221–251|doi=10.1146/annurev.cellbio.042308.113344|pmid=19575677|pmc=2861293}}</ref> RA signaling in this organism can affect the formation of the endoderm and depending on the timing of the signaling, it can determine the fate whether its pancreatic, intestinal, or respiratory. Other signals such as Wnt and BMP also play a role in respiratory fate of the ''Xenopus'' by activating cell lineage tracers.<ref name="Zorn A-2009"/>

==Amniotes==

===Overview===
In [[amniote]]s (reptiles, birds and mammals), gastrulation involves the creation of the blastopore, an opening into the [[archenteron]]. Note that the blastopore is not an opening into the [[blastocoel]], the space within the [[blastula]], but represents a new inpocketing that pushes the existing surfaces of the blastula together. In [[amniotes]], gastrulation occurs in the following sequence: (1) the [[embryo]] becomes [[asymmetry|asymmetric]]; (2) the [[primitive streak]] forms; (3) cells from the [[epiblast]] at the [[primitive streak]] undergo an [[Epithelial-mesenchymal transition|epithelial to mesenchymal transition]] and [[ingression (biology)|ingress]] at the [[primitive streak]] to form the [[germ layers]].<ref name=Arnold />

===Symmetry breaking===
In preparation for gastrulation, the embryo must become asymmetric along both the [[Anatomical_terms_of_location#Proximal_and_distal|proximal-distal axis]] and the [[Anatomical terms of location#Axes|anteroposterior axis]]. The proximal-distal axis is formed when the cells of the embryo form the "egg cylinder", which consists of the extraembryonic tissues, which give rise to structures like the [[placenta]], at the proximal end and the [[epiblast]] at the distal end.  Many signaling pathways contribute to this reorganization, including [[bone morphogenetic protein|BMP]], [[fibroblast growth factor|FGF]], [[nodal signaling|nodal]], and [[Wnt signaling pathway|Wnt]]. Visceral endoderm surrounds the [[epiblast]]. The [[Anatomical terms of location#Proximal and distal|distal]] visceral endoderm (DVE) migrates to the [[anterior]] portion of the embryo, forming the [[anterior visceral endoderm]] (AVE). This breaks anterior-posterior symmetry and is regulated by [[NODAL|nodal]] signaling.<ref name=Arnold />
[[File:Epithelial–mesenchymal transition scheme.png|thumb|right|[[Epithelial–mesenchymal transition]] – loss of cell adhesion leads to constriction and extrusion of newly formed [[mesenchymal]] cell.]]

===Germ layer determination===
The [[primitive streak]] is formed at the beginning of gastrulation and is found at the junction between the extraembryonic tissue and the [[epiblast]] on the posterior side of the embryo and the site of [[ingression (biology)|ingression]].<ref name=Tam>Tam & Behringer, 1997</ref> Formation of the [[primitive streak]] is reliant upon [[NODAL|nodal]] signaling<ref name=Arnold /> in the [[Koller's sickle]] within the cells contributing to the primitive streak and [[BMP4]] signaling from the extraembryonic tissue.<ref name=Tam /><ref name=catala2005>Catala, 2005: [https://books.google.com/books?id=RJvkR3gfExwC&pg=PA1535 p. 1535]</ref> Furthermore, [[Cerberus (protein)|Cer1]] and [[Lefty (protein)|Lefty1]] restrict the primitive streak to the appropriate location by antagonizing [[NODAL|nodal]] signaling.<ref name=Loebel>{{cite journal |author1=Tam, P.P.  |author2=Loebel, D.A|title=Gene function in mouse embryogenesis: get set for gastrulation | journal = Nat Rev Genet | volume = 8 | issue = 5 | pages = 368–81 | year = 2007 | pmid = 17387317 | doi = 10.1038/nrg2084|s2cid=138874}}</ref> The region defined as the [[primitive streak]] continues to grow towards the distal tip.<ref name=Arnold />

During the early stages of development, the primitive streak is the structure that will establish [[bilateral symmetry]], determine the site of gastrulation and initiate germ layer formation.<ref>{{Cite journal|last1=Sheng|first1=Guojun|last2=Arias|first2=Alfonso Martinez|last3=Sutherland|first3=Ann|date=2021-12-03|title=The primitive streak and cellular principles of building an amniote body through gastrulation|url=https://www.science.org/doi/abs/10.1126/science.abg1727|journal=Science|volume=374 |issue=6572 |pages=abg1727 |language=EN|doi=10.1126/science.abg1727|pmid=34855481 |s2cid=244841366 |url-access=subscription}}</ref> 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.<ref name="mikawa">{{cite journal |doi= 10.1002/dvdy.10458 |vauthors=Mikawa T, Poh AM, Kelly KA, Ishii Y, Reese DE |title= Induction and patterning of the primitive streak, an organizing center of gastrulation in the amniote. |journal= Dev Dyn |volume=229 |pages= 422–32|year=2004 |pmid=14991697| issue=3|s2cid=758473 |doi-access=free }}</ref> The primitive streak extends through this midline and creates the antero-posterior body axis,<ref name="downs">{{cite journal |doi= 10.1002/bies.200900038 |author= Downs KM. |title= The enigmatic primitive streak: prevailing notions and challenges concerning the body axis of mammals. |journal= BioEssays |volume=31 |pages= 892–902|year=2009|pmid=19609969| issue=8 |pmc= 2949267}}</ref> becoming the first symmetry-breaking event in the [[embryo]], and marks the beginning of gastrulation.<ref name="chuai">{{cite journal |vauthors=Chuai M, Zeng W, Yang X, Boychenko V, Glazier JA, Weijer CJ |title= Cell movement during chick primitive streak formation. |journal= Dev. Biol. |volume  =296|issue= 1 |pages= 137–49 |year=2006 |pmid=16725136 |pmc= 2556955 |doi= 10.1016/j.ydbio.2006.04.451}}</ref> This process involves the ingression of mesoderm and endoderm progenitors and their migration to their ultimate position,<ref name="downs"/><ref name="chuai M">{{cite book |doi= 10.1016/S0070-2153(07)81004-0 |vauthors=Chuai M, Weijer CJ |chapter=The mechanisms underlying primitive streak formation in the chick embryo. |title=Current Topics in Developmental Biology |volume= 81 |pages= 135–56 |year=2008 |pmid=18023726 |isbn=978-0-12-374253-7}}</ref> where they will differentiate  into the three germ layers.<ref name="mikawa"/> The localization of the cell adhesion and signaling molecule [[beta-catenin]] is critical to the proper formation of the organizer region that is responsible for initiating gastrulation.

===Cell internalization===
In order for the cells to move from the [[epithelium]] of the [[epiblast]] through the [[primitive streak]] to form a new layer, the cells must undergo an [[Epithelial-mesenchymal transition|epithelial to mesenchymal transition]] (EMT) to lose their epithelial characteristics, such as [[Cell adhesion|cell–cell adhesion]]. [[fibroblast growth factor|FGF]] signaling is necessary for proper EMT. [[FGFR1]] is needed for the up regulation of [[SNAI1]], which down regulates [[CDH1 (gene)|E-cadherin]], causing a loss of cell adhesion. Following the EMT, the cells [[ingression (biology)|ingress]] through the [[primitive streak]] and spread out to form a new layer of cells or join existing layers.  [[FGF8]] is implicated in the process of this dispersal from the [[primitive streak]].<ref name=Loebel />

== Cell signaling driving gastrulation ==
During gastrulation, the cells are differentiated into the ectoderm or [[mesendoderm]], which then separates into the mesoderm and endoderm.<ref name="Zorn A-2009"/> The endoderm and mesoderm form due to the [[nodal signaling]]. Nodal signaling uses ligands that are part of [[Transforming growth factor beta|TGFβ]] family. These ligands will signal transmembrane serine/threonine kinase receptors, and this will then phosphorylate [[Mothers against decapentaplegic homolog 2|Smad2]] and [[Mothers against decapentaplegic homolog 3|Smad3]]. This protein will then attach itself to [[Mothers against decapentaplegic homolog 4|Smad4]] and relocate to the nucleus where the mesendoderm genes will begin to be transcribed. The [[Wnt signaling pathway|Wnt pathway]] along with [[Beta-catenin|β-catenin]] plays a key role in nodal signaling and endoderm formation.<ref>{{Cite journal |pmid = 17307341|year = 2007|last1 = Grapin-Botton|first1 = A.|title = Evolution of the mechanisms and molecular control of endoderm formation|journal = Mechanisms of Development|volume = 124|issue = 4|pages = 253–78|last2 = Constam|first2 = D.|doi = 10.1016/j.mod.2007.01.001|s2cid = 16552755|doi-access = }}</ref> [[Fibroblast growth factor]]s (FGF), canonical Wnt pathway, [[bone morphogenetic protein]] (BMP), and [[retinoic acid]] (RA) are all important in the formation and development of the endoderm.<ref name="Zorn A-2009" /> FGF are important in producing the [[homeobox]] gene which regulates early anatomical development. BMP signaling plays a role in the liver and promotes hepatic fate. RA signaling also induce homeobox genes such as Hoxb1 and Hoxa5. In mice, if there is a lack in RA signaling the mouse will not develop lungs.<ref name="Zorn A-2009" /> RA signaling also has multiple uses in organ formation of the pharyngeal arches, the foregut, and hindgut.<ref name="Zorn A-2009" />

== Gastrulation ''in vitro'' ==
There have been a number of attempts to understand the processes of gastrulation using ''in vitro'' techniques in parallel and complementary to studies in embryos, usually though the use of [[Cell culture|2D]]<ref name="Turner-2014">{{Cite journal|last1=Turner|first1=David A.|last2=Rué|first2=Pau|last3=Mackenzie|first3=Jonathan P.|last4=Davies|first4=Eleanor|last5=Martinez Arias|first5=Alfonso|date=2014-01-01|title=Brachyury cooperates with Wnt/β-catenin signalling to elicit primitive-streak-like behaviour in differentiating mouse embryonic stem cells|journal=BMC Biology|volume=12|page=63|doi=10.1186/s12915-014-0063-7|issn=1741-7007|pmc=4171571|pmid=25115237 |doi-access=free }}</ref><ref name="Warmflash-2014">{{Cite journal|last1=Warmflash|first1=Aryeh|last2=Sorre|first2=Benoit|last3=Etoc|first3=Fred|last4=Siggia|first4=Eric D|last5=Brivanlou|first5=Ali H|title=A method to recapitulate early embryonic spatial patterning in human embryonic stem cells|journal=Nature Methods|volume=11|issue=8|pages=847–854|doi=10.1038/nmeth.3016|pmc=4341966|pmid=24973948|year=2014}}</ref><ref name="Etoc-2016">{{Cite journal|last1=Etoc|first1=Fred|last2=Metzger|first2=Jakob|last3=Ruzo|first3=Albert|last4=Kirst|first4=Christoph|last5=Yoney|first5=Anna|last6=Ozair|first6=M. Zeeshan|last7=Brivanlou|first7=Ali H.|last8=Siggia|first8=Eric D.|title=A Balance between Secreted Inhibitors and Edge Sensing Controls Gastruloid Self-Organization|journal=Developmental Cell|volume=39|issue=3|pages=302–315|doi=10.1016/j.devcel.2016.09.016|pmid=27746044|pmc=5113147|year=2016}}</ref> and 3D cell ([[Gastruloid|Embryonic organoids]]) culture techniques<ref name="Brink-2014">{{Cite journal|last1=Brink|first1=Susanne C. van den|last2=Baillie-Johnson|first2=Peter|last3=Balayo|first3=Tina|last4=Hadjantonakis|first4=Anna-Katerina|last5=Nowotschin|first5=Sonja|last6=Turner|first6=David A.|last7=Arias|first7=Alfonso Martinez|date=2014-11-15|title=Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells|journal=Development|language=en|volume=141|issue=22|pages=4231–4242|doi=10.1242/dev.113001|issn=0950-1991|pmc=4302915|pmid=25371360}}</ref><ref name="Turner-2016">{{Cite bioRxiv|last1=Turner|first1=David Andrew|last2=Glodowski|first2=Cherise R.|last3=Luz|first3=Alonso-Crisostomo|last4=Baillie-Johnson|first4=Peter|last5=Hayward|first5=Penny C.|last6=Collignon|first6=Jérôme|last7=Gustavsen|first7=Carsten|last8=Serup|first8=Palle|last9=Schröter|first9=Christian|date=2016-05-13|title=Interactions between Nodal and Wnt signalling Drive Robust Symmetry Breaking and Axial Organisation in Gastruloids (Embryonic Organoids)|biorxiv=10.1101/051722}}</ref><ref name="Turner-2017">{{Cite bioRxiv|last1=Turner|first1=David|last2=Alonso-Crisostomo|first2=Luz|last3=Girgin|first3=Mehmet|last4=Baillie-Johnson|first4=Peter|last5=Glodowski|first5=Cherise R.|last6=Hayward|first6=Penelope C.|last7=Collignon|first7=Jérôme|last8=Gustavsen|first8=Carsten|last9=Serup|first9=Palle|date=2017-01-31|title=Gastruloids develop the three body axes in the absence of extraembryonic tissues and spatially localised signalling|biorxiv=10.1101/104539}}</ref><ref>{{Cite journal|last1=Beccari|first1=Leonardo|last2=Moris|first2=Naomi|last3=Girgin|first3=Mehmet|last4=Turner|first4=David A.|last5=Baillie-Johnson|first5=Peter|last6=Cossy|first6=Anne-Catherine|last7=Lutolf|first7=Matthias P.|last8=Duboule|first8=Denis|last9=Arias|first9=Alfonso Martinez|date=October 2018|title=Multi-axial self-organization properties of mouse embryonic stem cells into gastruloids|journal=Nature|language=En|volume=562|issue=7726|pages=272–276|doi=10.1038/s41586-018-0578-0|pmid=30283134|issn=0028-0836|bibcode=2018Natur.562..272B|s2cid=52915553|url=https://www.repository.cam.ac.uk/handle/1810/285960}}</ref> using [[embryonic stem cell]]s (ESCs) or [[induced pluripotent stem cell]]s (iPSCs). These are associated with number of clear advantages in using tissue-culture based protocols, some of which include reducing the cost of associated ''in vivo'' work (thereby reducing, replacing and refining the use of animals in experiments; [[Three Rs (animal research)|the 3Rs]]), being able to accurately apply agonists/antagonists in spatially and temporally specific manner<ref name="Turner-2016" /><ref name="Turner-2017" /> which may be technically difficult to perform during Gastrulation. However, it is important to relate the observations in culture to the processes occurring in the embryo for context.

To illustrate this, the guided differentiation of mouse ESCs has resulted in generating [[primitive streak]]–like cells that display many of the characteristics of epiblast cells that traverse through the primitive streak<ref name="Turner-2014" /> (e.g. transient [[brachyury]] up regulation and the cellular changes associated with an [[Epithelial–mesenchymal transition|epithelial to mesenchymal transition]]<ref name="Turner-2014" />), and human ESCs cultured on micro patterns, treated with [[Bone morphogenetic protein 4|BMP4]], can generate spatial differentiation pattern similar to the arrangement of the [[germ layer]]s in the human embryo.<ref name="Warmflash-2014" /><ref name="Etoc-2016" /> Finally, using 3D [[embryoid body]]- and [[organoid]]-based techniques, small aggregates of mouse ESCs ([[Gastruloid|Embryonic Organoids, or Gastruloids]]) are able to show a number of processes of early mammalian embryo development such as symmetry-breaking, polarisation of gene expression, gastrulation-like movements, axial elongation and the generation of all three embryonic axes (anteroposterior, dorsoventral and left-right axes).<ref name="Brink-2014" /><ref name="Turner-2016" /><ref name="Turner-2017" /><ref>{{Cite journal|last1=Turner|first1=David A.|last2=Girgin|first2=Mehmet|last3=Alonso-Crisostomo|first3=Luz|last4=Trivedi|first4=Vikas|last5=Baillie-Johnson|first5=Peter|last6=Glodowski|first6=Cherise R.|last7=Hayward|first7=Penelope C.|last8=Collignon|first8=Jérôme|last9=Gustavsen|first9=Carsten|date=2017-11-01|title=Anteroposterior polarity and elongation in the absence of extra-embryonic tissues and of spatially localised signalling in gastruloids: mammalian embryonic organoids|journal=Development|language=en|volume=144|issue=21|pages=3894–3906|doi=10.1242/dev.150391|issn=0950-1991|pmid=28951435|pmc=5702072}}</ref>

In ''vitro'' fertilization occurs in a laboratory. The process of in ''vitro'' fertilization is when mature eggs are removed from the ovaries and are placed in a cultured medium where they are fertilized by sperm. In the culture the embryo will form.<ref>{{Cite web |title=In vitro fertilization (IVF) - Mayo Clinic |url=https://www.mayoclinic.org/tests-procedures/in-vitro-fertilization/about/pac-20384716 |access-date=2022-04-11 |website=www.mayoclinic.org}}</ref> 14 days after fertilization the primitive streak forms. The formation of the primitive streak has been known to some countries as "human individuality".<ref>{{Cite journal |last=Asplund |first=Kjell |date=2020 |title=Use of in vitro fertilization—ethical issues |url=https://ujms.net/index.php/ujms/article/view/5673 |journal=Upsala Journal of Medical Sciences |language=en |volume=125 |issue=2 |pages=192–199 |doi=10.1080/03009734.2019.1684405 |pmid=31686575 |pmc=7721055 |s2cid=207896932 |issn=2000-1967}}</ref> This means that the embryo is now a being itself, it is its own entity. The countries that believe this have created a 14-day rule in which it is illegal to study or experiment on a human embryo after the 14-day period in ''vitro''. Research has been conducted on the first 14 days of an embryo, but no known studies have been done after the 14 days.<ref>{{Cite journal |last=Davis |first=Caitlin |date=2019-03-01 |title=The Boundaries of Embryo Research: Extending the Fourteen-Day Rule |journal=Journal of Bioethical Inquiry |language=en |volume=16 |issue=1 |pages=133–140 |doi=10.1007/s11673-018-09895-w |pmid=30635823 |s2cid=58643344 |issn=1872-4353}}</ref> With the rule in place, mice embryos are used understand the development after 14 days; however, there are differences in the development between mice and humans. 

==See also==
* [[Fate mapping]]
* [[Primitive node]]
* [[Neurulation]]
* [[Vegetal rotation]]

==References==

===Notes===
{{Reflist}}

===Bibliography===
* {{cite journal | author1=Arnold, Sebastian J. | author2=Robertson, Elizabeth J. | author-link2=Elizabeth Robertson | title=Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo | journal=[[Nat. Rev. Mol. Cell Biol.]] | volume=10 | issue=2 | pages=91–103 | year=2009 | pmid=19129791 | doi=10.1038/nrm2618 | s2cid=94174 }}{{closed access}}
* {{cite book | author=Catala, Martin | chapter=Embryology of the Spine and Spinal Cord |editor1=Tortori-Donati, Paolo |display-editors=etal | title=Pediatric Neuroradiology: Brain | publisher=Springer | year=2005 | isbn=978-3-540-41077-5 | url=https://books.google.com/books?id=RJvkR3gfExwC | chapter-url=https://books.google.com/books?id=RJvkR3gfExwC&pg=PA1535 }}
* {{Cite book | author=Ereskovsky, Alexander V. | title=The Comparative Embryology of Sponges | publisher=Springer | year=2010 | isbn=978-90-481-8574-0 | url=https://books.google.com/books?id=PHztG3LEUnsC }}
* {{Cite book | author=Gilbert, Scott F. |title=Developmental Biology | edition=Ninth | publisher=Sinauer Associates | year=2010 | isbn=978-0-87893-558-1 }}
* {{cite book | author=Hall, Brian Keith | author-link=Brian K. Hall | title=Evolutionary developmental biology | chapter=8.3.3 The gastrula and gastrulation | chapter-url=https://books.google.com/books?id=JhSwumfgTQ4C&pg=PA132 | publisher=Kluwer Academic Publishers | edition=2nd | location=The Netherlands | year=1998 | isbn=978-0-412-78580-1 | url=https://books.google.com/books?id=JhSwumfgTQ4C }}
* {{cite book | author=Harrison, Lionel G. | author-link=Lionel G. Harrison | title=The Shaping of Life: The Generation of Biological Pattern | publisher=Cambridge University Press | year=2011 | isbn=978-0-521-55350-6 | url=https://books.google.com/books?id=-IPG-vg7Pr8C }}
* {{cite book | editor=McGeady, Thomas A. | chapter=Gastrulation | title=Veterinary embryology | publisher=Wiley-Blackwell | year=2006 | isbn=978-1-4051-1147-8 | url=https://books.google.com/books?id=n4C0TUeR7mUC&pg=PA34 | chapter-url=<!--no ebook access available; therefore not link to start of chapter --> }}
* {{Cite book | author=Mundlos, Stefan | chapter=Gene action: developmental genetics |editor1=Speicher, Michael |display-editors=etal | title=Vogel and Motulsky's Human Genetics: Problems and Approaches | edition=4th | publisher=Springer | year=2009 | isbn=978-3-540-37653-8 | doi=10.1007/978-3-540-37654-5 | url=https://books.google.com/books?id=FlfPSpBvKLgC | chapter-url=<!-- the page for the start of the chapter is not available for viewing, unfortunately--> }}
* {{cite journal |author1=Tam, Patrick P.L.  |author2=Behringer, Richard R. | title=Mouse gastrulation: the formation of a mammalian body plan | journal=[[Mech. Dev.]] | volume=68 | issue=1–2 | pages=3–25 | year=1997 | pmid=9431800| doi=10.1016/S0925-4773(97)00123-8 |s2cid=14052942 | doi-access=free }}{{open access}}

==Further reading==
<!-- {{cite book|chapter=|title=|publisher=|year=|isbn=|pages=|url=}} -->
* {{cite book|author=Baron, Margaret H.|chapter=Embryonic Induction of Mammalian Hematopoiesis and Vasculogenesis|editor=Zon, Leonard I.|title=Hematopoiesis: a developmental approach|publisher=Oxford University Press|year=2001|isbn=978-0-19-512450-7|chapter-url=https://books.google.com/books?id=zolYg-SsVhQC&pg=PA162}}
* {{cite book|author=Cullen, K.E.|chapter=embryology and early animal development|title=Encyclopedia of life science, Volume 2|publisher=Infobase|year=2009|isbn=978-0-8160-7008-4|chapter-url=https://books.google.com/books?id=iM_O62qBSQYC&pg=PA283}}
* {{cite book|author1=Forgács, G. |author2=Newman, Stuart A. |chapter=Cleavage and blastula formation|title=Biological physics of the developing embryo|publisher=Cambridge University Press|year=2005|isbn=978-0-521-78337-8|chapter-url=https://books.google.com/books?id=rUyVWQhk7CkC&pg=PA24|bibcode=2005bpde.book.....F}}
* {{cite book|author1=Forgács, G. |author2=Newman, Stuart A. |chapter=Epithelial morphogenesis: gastrulation and neurulation|title=Biological physics of the developing embryo|publisher=Cambridge University Press|year=2005|isbn=978-0-521-78337-8|chapter-url=https://books.google.com/books?id=rUyVWQhk7CkC&pg=PA99|bibcode=2005bpde.book.....F}}
* {{cite book|author1=Hart, Nathan H. |author2=Fluck, Richard A. |chapter=Epiboly and Gastrulation|editor=Capco, David|title=Cytoskeletal mechanisms during animal development|publisher=Academic Press|year=1995|isbn=978-0-12-153131-7|chapter-url=https://books.google.com/books?id=v2lAYAEZrgsC&pg=PA362|url-access=registration|url=https://archive.org/details/cytoskeletalmech0000capc}}
* {{cite book|author=Knust, Elizabeth|chapter=Gastrulation movements|editor=Birchmeier, Walter |editor2=Birchmeier, Carmen |title=Epithelial Morphogenesis in Development and Disease|publisher=CRC Press|year=1999|isbn=978-90-5702-419-1|pages=152–153|chapter-url=https://books.google.com/books?id=auK62QPZOWkC&pg=PA152}}
* {{cite book|author=Kunz, Yvette W.|chapter=Gastrulation|title=Developmental biology of Teleost fishes|publisher=Springer|year=2004|isbn=978-1-4020-2996-7|chapter-url=https://books.google.com/books?id=BWsrvViQmw0C&pg=PA207}}
* {{cite book|chapter=Gastrulation|editor=Nation, James L.|title=Insect physiology and biochemistry|publisher=CRC Press|year=2009|isbn=978-0-8493-1181-9|chapter-url=https://books.google.com/books?id=l3v2tOvz1uQC&pg=PA9}}
* {{cite book|chapter=Human Ontogeny: Gastrulation, Neurulation, and Somite Formation|editor=Ross, Lawrence M. |editor2=Lamperti, Edward D.|title=Atlas of anatomy: general anatomy and musculoskeletal system|publisher=Thieme|year=2006|isbn=978-3-13-142081-7|chapter-url=https://books.google.com/books?id=NK9TgTaGt6UC&pg=PA6}}
* {{cite book|author=Sanes, Dan H.|chapter=Early embryology of metazoans|title=Development of the nervous system|edition=2nd|publisher=Academic Press|year=2006|isbn=978-0-12-618621-5|pages=1–2|chapter-url=https://books.google.com/books?id=7q1XsiiIeNwC&pg=PA3|display-authors=etal}}
* {{cite book|author1=Stanger, Ben Z. |author2=Melton, Douglas A. |chapter=Development of Endodermal Derivatives in the Lungs, Liver, Pancreas, and Gut|editor1=Epstein, Charles J. |display-editors=etal |title=Inborn errors of development: the molecular basis of clinical disorders of morphogenesis|publisher=Oxford University Press|year=2004|isbn=978-0-19-514502-1|chapter-url=https://books.google.com/books?id=wGoj9RtTcVIC&pg=PA182}}

==External links==
* [http://learningobjects.wesleyan.edu/gastrulation/ Gastrulation animations] {{Webarchive|url=https://web.archive.org/web/20151020033205/http://learningobjects.wesleyan.edu/gastrulation/ |date=2015-10-20 }}
* [http://www.gastrulation.org Gastrulation illustrations and movies from Gastrulation: From Cells To Embryo edited by Claudio Stern]
* [http://www.gastrulation.org/Movie13_1.mov A video of frog gastrulation]
{{Embryology}}
{{Authority control}}

[[Category:Gastrulation]]
[[Category:Animal developmental biology]]
[[Category:Embryology]]