Gastrulation

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Introduction

Human embryo primitive streak
Hans Spemann (1869 - 1941)

The term gastrulation means the formation of gut (Greek, gastrula = belly), but has now a more broad sense to to describe the formation of the trilaminar embryo. The epiblast layer, consisting of totipotential cells, derives all 3 embryo layers: ectoderm, mesoderm and endoderm. The primitive streak is the visible feature which represents the site of cell migration to form the additional layers.


Historically, gastrulation was one of the earliest observable morphological event occurring in the frog embryo. Currently, the molecular and physical mechanisms that regulate patterning and migration during this key event are being investigated in several different animal models. This region was also called the "Spemann's organiser" after Hans Spemann (1869 - 1941) who identified the region in amphibia. The same region in birds it is known as "Hensen's node" named for Victor Hensen (1835 – 1924) and is also known generally as the primitive node or knot. In humans, it is proposed that similar mechanisms regulate gastrulation to those found in other vertebrates.


  • primitive node - region in the middle of the early embryonic disc epiblast from which the primitive streak extends caudally (tail)
    • nodal cilia establish the embryo left/right axis
    • axial process extends from the nodal epiblast
  • primitive streak - region of cell migration from the epiblast layer forming sequentially the two germ cell layers (endoderm and mesoderm)


Signaling Pathway: BMP4 -> Wnt -> Activin–Nodal

Human BMP Family  
Table - Human Bmp Family
Approved
Symbol
Approved Name Previous
Symbols
Synonyms Chromosome
BMP1 bone morphogenetic protein 1 PCOLC 8p21.3
BMP2 bone morphogenetic protein 2 BMP2A 20p12.3
BMP3 bone morphogenetic protein 3 4q21.21
BMP4 bone morphogenetic protein 4 BMP2B 14q22.2
BMP5 bone morphogenetic protein 5 6p12.1
BMP6 bone morphogenetic protein 6 VGR VGR1 6p24.3
BMP7 bone morphogenetic protein 7 OP-1 20q13.31
BMP8A bone morphogenetic protein 8a 1p34.3
BMP8B bone morphogenetic protein 8b BMP8 OP-2 1p34.2
BMP10 bone morphogenetic protein 10 2p13.3
BMP15 bone morphogenetic protein 15 GDF9B Xp11.22
    Links: Developmental Signals - Bone Morphogenetic Protein | OMIM BMP2 | HGNC | Bmp Family | Sox Family | Tbx Family
Human R-spondin Family  
Table - Human R-spondin Family
Approved
Symbol
Approved Name Previous
Symbols
Synonyms Chromosome
RSPO1 R-spondin 1 FLJ40906, RSPONDIN 1p34.3
RSPO2 R-spondin 2 MGC35555 8q23.1
RSPO3 R-spondin 3 THSD2 FLJ14440 6q22.33
RSPO4 R-spondin 4 C20orf182 dJ824F16.3 20p13
    Links: Developmental Signals - Wnt | Bmp Family | Fgf Family | Pax Family | R-spondin Family | Sox Family | Tbx Family | Wnt Family

Inhibitors - Wnt inhibitor IWP2; Nodal inhibitor (SB431542 drug TGF-beta/Smad inhibitor)

Epithelial to Mesenchymal Transition

Gastrulation cartoon

Epithelial cells (organised cellular layer) which loose their organisation and migrate/proliferate as a mesenchymal cells (disorganised cellular layers) are said to have undergone an Epithelial Mesenchymal Transition (EMT). Mesenchymal cells have an embryonic connective tissue-like cellular arrangement, that have undergone this process may at a later time and under specific signaling conditions undergo the opposite process, mesenchyme to epithelia. In development, this process can be repeated several times during tissue differentiation.

This process occurs at the primitive streak where epiblast cells undergo an epithelial to mesenchymal transition in order to delaminate and migrate.


Links: gastrulation | Lecture - Week 3 | Week 3 | Carnegie stage 7 | Carnegie 8 | endoderm | mesoderm | ectoderm | Epithelial Mesenchymal Transition | notochord
Historic Embryology - Gastrulation 
Historic Papers: 1910 Gastrulation | 1935 Nobel Lecture | 1951 Frog Gastrulation

Some Recent Findings

  • Self-organization of a human organizer by combined Wnt and Nodal signalling[1] "In amniotes, the development of the primitive streak and its accompanying 'organizer' define the first stages of gastrulation. Although these structures have been characterized in detail in model organisms, the human primitive streak and organizer remain a mystery. When stimulated with BMP4, micropatterned colonies of human embryonic stem cells self-organize to generate early embryonic germ layers 1 . Here we show that, in the same type of colonies, Wnt signalling is sufficient to induce a primitive streak, and stimulation with Wnt and Activin is sufficient to induce an organizer, as characterized by embryo-like sharp boundary formation, markers of epithelial mesenchymal transition and expression of the organizer-specific transcription factor GSC. Moreover, when grafted into chick embryos, human stem cell colonies treated with Wnt and Activin induce and contribute autonomously to a secondary axis while inducing a neural fate in the host."
  • Molecular regulation of Nodal signaling during mesendoderm formation[2] "One of the most important events during vertebrate embryogenesis is the formation or specification of the three germ layers, endoderm, mesoderm, and ectoderm. After a series of rapid cleavages, embryos form the mesendoderm and ectoderm during late blastulation and early gastrulation. The mesendoderm then further differentiates into the mesoderm and endoderm. Nodal, a member of the transforming growth factor β (TGF-beta, TGF-β) superfamily, plays a pivotal role in mesendoderm formation by regulating the expression of a number of critical transcription factors, including Mix-like, GATA, Sox, and Fox. Because the Nodal signal transduction pathway is well-characterized, increasing effort has been made to delineate the spatiotemporal modulation of Nodal signaling during embryonic development. In this review, we summarize the recent progress delineating molecular regulation of Nodal signal intensity and duration during mesendoderm formation." TGF-beta
  • BMP and FGF signaling interact to pattern mesoderm by controlling basic helix-loop-helix transcription factor activity[3] "The mesodermal germ layer is patterned into mediolateral subtypes by signaling factors including BMP and FGF. How these pathways are integrated to induce specific mediolateral cell fates is not well understood. We used mesoderm derived from post-gastrulation neuromesodermal progenitors (NMPs), which undergo a binary mediolateral patterning decision, as a simplified model to understand how FGF acts together with BMP to impart mediolateral fate. Using zebrafish and mouse NMPs, we identify an evolutionarily conserved mechanism of BMP and FGF mediated mediolateral mesodermal patterning that occurs through modulation of basic helix-loop-helix (bHLH) transcription factor activity. BMP imparts lateral fate through induction of Id helix loop helix (HLH) proteins, which antagonize bHLH transcription factors, induced by FGF signaling, that specify medial fate. We extend our analysis of zebrafish development to show that bHLH activity is responsible for the mediolateral patterning of the entire mesodermal germ layer."
  • Review - Molecular specification of germ layers in vertebrate embryos[4] "In order to generate the tissues and organs of a multicellular organism, different cell types have to be generated during embryonic development. The first step in this process of cellular diversification is the formation of the three germ layers: ectoderm, endoderm and mesoderm. The ectoderm gives rise to the nervous system, epidermis and various neural crest-derived tissues, the endoderm goes on to form the gastrointestinal, respiratory and urinary systems as well as many endocrine glands, and the mesoderm will form the notochord, axial skeleton, cartilage, connective tissue, trunk muscles, kidneys and blood. Classic experiments in amphibian embryos revealed the tissue interactions involved in germ layer formation and provided the groundwork for the identification of secreted and intracellular factors involved in this process."
  • Rho kinase activity controls directional cell movements during primitive streak formation in the rabbit embryo[5] "During animal gastrulation, the specification of the embryonic axes is accompanied by epithelio-mesenchymal transition (EMT), the first major change in cell shape after fertilization. EMT takes place in disparate topographical arrangements, such as the circular blastopore of amphibians, the straight primitive streak of birds and mammals or in intermediate gastrulation forms of other amniotes such as reptiles. Planar cell movements are prime candidates to arrange specific modes of gastrulation but there is no consensus view on their role in different vertebrate classes. Here, we test the impact of interfering with Rho kinase-mediated cell movements on gastrulation topography in blastocysts of the rabbit, which has a flat embryonic disc typical for most mammals. Time-lapse video microscopy, electron microscopy, gene expression and morphometric analyses of the effect of inhibiting ROCK activity showed - besides normal specification of the organizer region - a dose-dependent disruption of primitive streak formation; this disruption resulted in circular, arc-shaped or intermediate forms, reminiscent of those found in amphibians, fishes and reptiles. Our results reveal a crucial role of ROCK-controlled directional cell movements during rabbit primitive streak formation and highlight the possibility that temporal and spatial modulation of cell movements were instrumental for the evolution of gastrulation forms." rabbit


More recent papers  
Mark Hill.jpg
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches


Search term: Gastrulation

Philip L Hertzler, Jiankai Wei, Andrew P Droste, Jianbo Yuan, Jianhai Xiang Penaeid shrimp brachyury: sequence analysis and expression during gastrulation. Dev. Genes Evol.: 2018; PubMed 30121809

I V Korobko, M V Shepelev [Mutations in the Effector Domain of RhoV GTPase Impair Its Binding to Pak1 Protein Kinase]. Mol. Biol. (Mosk.): 2017, 52(4);692-698 PubMed 30113035

Amanda Janesick, Weiyi Tang, Toshi Shioda, Bruce Blumberg RARγ is required for mesodermal gene expression prior to gastrulation. Development: 2018; PubMed 30111657

Zairan Liu, Stephanie Woo, Orion D Weiner Nodal signaling has dual roles in fate specification and directed migration during germ layer segregation. Development: 2018; PubMed 30111654

Kristen S Barratt, Koula E M Diamand, Ruth M Arkell Identification of reference genes suitable for RT-qPCR studies of murine gastrulation and patterning. Mamm. Genome: 2018; PubMed 30094508

Older papers  
  • Generation of organized germ layers from a single mouse embryonic stem cell[6] "Mammalian inner cell mass cells undergo lineage-specific differentiation into germ layers of endoderm, mesoderm and ectoderm during gastrulation. It has been a long-standing challenge in developmental biology to replicate these organized germ layer patterns in culture. Here we present a method of generating organized germ layers from a single mouse embryonic stem cell cultured in a soft fibrin matrix." stem cells
  • Deficiency in crumbs homolog 2 (Crb2) affects gastrulation and results in embryonic lethality in mice[7] "The Crumbs family of transmembrane proteins has an important role in the differentiation of the apical membrane domain in various cell types, regulating such processes as epithelial cell polarization. The mammalian Crumbs protein family is composed of three members. Here, we inactivated the mouse Crb2 gene with gene-targeting techniques and found that the protein is crucial for early embryonic development with severe abnormalities appearing in Crb2-deficient embryos at late-gastrulation. Our findings indicate that the primary defect in the mutant embryos is disturbed polarity of the epiblast cells at the primitive streak, which affects epithelial to mesenchymal transition (EMT) during gastrulation, resulting in impaired mesoderm and endoderm formation, and embryonic lethality by embryonic day 12.5. These findings therefore indicate a novel role for the Crumbs family of proteins."
  • Zebrafish eve1 regulates the lateral and ventral fates of mesodermal progenitor cells at the onset of gastrulation[8] "Our data show that Eve1 functions together with Ved, Vent and Vox in a transcriptional network to prevent the spread of anti-Bmp gene activity from the dorsal side, leading to the establishment of the Bmp gradient activity along the dorsoventral axis to induce distinct transcriptional outputs in mesodermal progenitor cells (MPCs) to maintain the lateral and ventral MPC fates during gastrulation."

Gastrulation Movies

Animation showing the secondary spread of mesoderm following the migration of endoderm through the primitive streak.
Mesoderm 001 icon.jpg
 ‎‎Week 3 Mesoderm
Page | Play
Nodal-cilia-001-icon.jpg
 ‎‎Nodal Cilia
Page | Play
Quail HH stage 2 fibronectin movement.jpg
 ‎‎Gastrulation ECM
Page | Play
Gastrulation planar cell move icon.jpg
 ‎‎Planar Movement
Page | Play
Mesoderm migration movie 1 icon.jpg
 ‎‎Mesoderm Move
Page | Play
mesoderm spread mouse cilia quail extracellular matrix Planar cell movement Mesoderm migration

Human Gastrulation

The site of gastrulation, the primitive streak is visible during week 3 on the epiblast dorsal surface of the embryonic disc.

Stage 7

Stage7-sem4.jpg Stage7-bf4.jpg

Stage7 primitive streak labelled.jpg


Links: Carnegie stage 7

Stage 8

Stage8 bf10.jpg

Primitive pit

Stage8 bf11.jpg

Primitive groove and primitive streak


Links: Carnegie stage 8

Gastrulation Concepts

Chicken-gastrulation2.jpg


Chicken-gastrulation3.jpg


Links: Chicken Development


Germ Layer Markers

Stem cell researchers have used the following markers to identify early differentiation of cells in the three germ layer in embryoid bodies.[9]


Links: Induced Stem Cells | Alpha-Fetoprotein

Frog Gastrulation

Rugh 071.jpg Frog Gastrulation[10]

(A) The blastula stage, prior to any gastrulation movement.

(B) Movement of the blastula cells preliminary to gastrulation.

(C) Blastoporal view of successive phases of gastrulation; (solid line) lip of blastopore, {dotted line) germ ring, to be subsequently incorporated into the blastoporal lips.

(D) Lateral view of sagittal section during late gastrulation showing the origin of the mesial notochord, and the lateral mesoderm from the proliferated chorda-mesoderm cells at the dorsal lip.

(E) Composite drawing to illustrate the germ layer relations in the later gastrula of the frog. The medullary plate (ectoderm) is not indicated; {alternate dots and dashes) notochord, {heavy stippling) notochord, {sparse stippling) mesoderm, (cellular markings) ectoderm.

Links: Frog Development

Zebrafish Gastrulation

Kupffer's vesicle (ciliated organ of asymmetry, primitive node) a transient epithelial fluid-filled sac located midventrally posterior to the yolk cell or its extension. The vesicle has been described as equivalent to the primitive node for establishing embryo left-right (L-R) axis.[11]

Links: Zebrafish Development

Additional Images

References

  1. Martyn I, Kanno TY, Ruzo A, Siggia ED & Brivanlou AH. (2018). Self-organization of a human organizer by combined Wnt and Nodal signalling. Nature , 558, 132-135. PMID: 29795348 DOI.
  2. Wei S & Wang Q. (2018). Molecular regulation of Nodal signaling during mesendoderm formation. Acta Biochim. Biophys. Sin. (Shanghai) , 50, 74-81. PMID: 29206913 DOI.
  3. Row RH, Pegg A, Kinney B, Farr GH, Maves L, Lowell S, Wilson V & Martin BL. (2018). BMP and FGF signaling interact to pattern mesoderm by controlling basic helix-loop-helix transcription factor activity. Elife , 7, . PMID: 29877796 DOI.
  4. Kiecker C, Bates T & Bell E. (2016). Molecular specification of germ layers in vertebrate embryos. Cell. Mol. Life Sci. , 73, 923-47. PMID: 26667903 DOI.
  5. Stankova V, Tsikolia N & Viebahn C. (2015). Rho kinase activity controls directional cell movements during primitive streak formation in the rabbit embryo. Development , 142, 92-8. PMID: 25516971 DOI.
  6. Poh YC, Chen J, Hong Y, Yi H, Zhang S, Chen J, Wu DC, Wang L, Jia Q, Singh R, Yao W, Tan Y, Tajik A, Tanaka TS & Wang N. (2014). Generation of organized germ layers from a single mouse embryonic stem cell. Nat Commun , 5, 4000. PMID: 24873804 DOI.
  7. Xiao Z, Patrakka J, Nukui M, Chi L, Niu D, Betsholtz C, Pikkarainen T, Pikkarainan T, Vainio S & Tryggvason K. (2011). Deficiency in Crumbs homolog 2 (Crb2) affects gastrulation and results in embryonic lethality in mice. Dev. Dyn. , 240, 2646-56. PMID: 22072575 DOI.
  8. Seebald JL & Szeto DP. (2011). Zebrafish eve1 regulates the lateral and ventral fates of mesodermal progenitor cells at the onset of gastrulation. Dev. Biol. , 349, 78-89. PMID: 20950598 DOI.
  9. Pekkanen-Mattila M, Pelto-Huikko M, Kujala V, Suuronen R, Skottman H, Aalto-Setälä K & Kerkelä E. (2010). Spatial and temporal expression pattern of germ layer markers during human embryonic stem cell differentiation in embryoid bodies. Histochem. Cell Biol. , 133, 595-606. PMID: 20369364 DOI.
  10. Rugh R. Book - The Frog Its Reproduction and Development. (1951) The Blakiston Company.
  11. Gao W, Xu L, Guan R, Liu X, Han Y, Wu Q, Xiao Y, Qi F, Zhu Z, Lin S & Zhang B. (2011). Wdr18 is required for Kupffer's vesicle formation and regulation of body asymmetry in zebrafish. PLoS ONE , 6, e23386. PMID: 21876750 DOI.


Reviews

Tseng WC, Munisha M, Gutierrez JB & Dougan ST. (2017). Establishment of the Vertebrate Germ Layers. Adv. Exp. Med. Biol. , 953, 307-381. PMID: 27975275 DOI.

Kiecker C, Bates T & Bell E. (2016). Molecular specification of germ layers in vertebrate embryos. Cell. Mol. Life Sci. , 73, 923-47. PMID: 26667903 DOI.

Nowotschin S & Hadjantonakis AK. (2010). Cellular dynamics in the early mouse embryo: from axis formation to gastrulation. Curr. Opin. Genet. Dev. , 20, 420-7. PMID: 20566281 DOI.

Chenoweth JG, McKay RD & Tesar PJ. (2010). Epiblast stem cells contribute new insight into pluripotency and gastrulation. Dev. Growth Differ. , 52, 293-301. PMID: 20298258 DOI.

Thiery JP, Acloque H, Huang RY & Nieto MA. (2009). Epithelial-mesenchymal transitions in development and disease. Cell , 139, 871-90. PMID: 19945376 DOI.

Roszko I, Sawada A & Solnica-Krezel L. (2009). Regulation of convergence and extension movements during vertebrate gastrulation by the Wnt/PCP pathway. Semin. Cell Dev. Biol. , 20, 986-97. PMID: 19761865 DOI.

Rohrschneider MR & Nance J. (2009). Polarity and cell fate specification in the control of Caenorhabditis elegans gastrulation. Dev. Dyn. , 238, 789-96. PMID: 19253398 DOI.

Heisenberg CP & Solnica-Krezel L. (2008). Back and forth between cell fate specification and movement during vertebrate gastrulation. Curr. Opin. Genet. Dev. , 18, 311-6. PMID: 18721878 DOI.

Watters C. (2005). Video views and reviews: gastrulation and the fashioning of animal embryos. Cell Biol Educ , 4, 273-8. PMID: 16344860 DOI.

Viebahn C. (2001). Hensen's node. Genesis , 29, 96-103. PMID: 11170350

Leptin M. (1999). Gastrulation in Drosophila: the logic and the cellular mechanisms. EMBO J. , 18, 3187-92. PMID: 10369659 DOI.

Articles

Chuai M, Hughes D & Weijer CJ. (2012). Collective epithelial and mesenchymal cell migration during gastrulation. Curr. Genomics , 13, 267-77. PMID: 23204916 DOI.

Halacheva V, Fuchs M, Dönitz J, Reupke T, Püschel B & Viebahn C. (2011). Planar cell movements and oriented cell division during early primitive streak formation in the mammalian embryo. Dev. Dyn. , 240, 1905-16. PMID: 21761476 DOI.

Vasiev B, Balter A, Chaplain M, Glazier JA & Weijer CJ. (2010). Modeling gastrulation in the chick embryo: formation of the primitive streak. PLoS ONE , 5, e10571. PMID: 20485500 DOI.

Books

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Cite this page: Hill, M.A. (2018, August 21) Embryology Gastrulation. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Gastrulation

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