Developmental Mechanism - Epithelial Mesenchymal Transition

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Introduction

Gastrulation epithelial to mesenchymal transition

The term epithelial mesenchymal transition (EMT) refers to a developmental process where an established epithelium either "breaks down" or "delaminates" allowing cells to leave the epithelium and become connective tissue (mesenchymal) in organisation. This transition can be a permanent change, or a transient event, where the mesenchymal cells may reestablish a new epithelial organisation (mesenchymal epithelial transition).


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, connective tissue-like, that have undergone this process may at a later time and under specific signaling can undergo the opposite process, mesenchyme to epithelia. In development, this process can be repeated several times during tissue differentiation. For example, within the mesoderm somite epithelium, the sclerotome component undergoes EMT forming the skeletal elements of the vertebrae and ribs. Other examples occur in neural crest formation, heart valve formation and Müllerian duct regression.

Mechanism - "a process, technique, or system for achieving a result".


This process is also studied in carcinogenesis (oncogenesis) or cancer development, where part of this process can be the transformation of an epithelial cell into a mesenchymal cell.[1][2]


Historically, in the late 1970s Elizabeth Hay began studied “epithelial–mesenchymal transformation” in embryogenesis.[3]


Mechanism Links: mitosis | cell migration | cell junctions |epithelial invagination | epithelial mesenchymal transition | mesenchymal epithelial transition | epithelial mesenchymal interaction | morphodynamics | tube formation | apoptosis | autophagy | axes formation | time | molecular

Some Recent Findings

  • Sox9 promotes renal tubular epithelial‑mesenchymal transition and extracellular matrix aggregation via the PI3K/AKT signaling pathway[4] "Sox9 is important for multiple aspects of development, such as testis, pancreas and heart development. Previous studies have reported that Sox9 induced epithelial‑mesenchymal transition (EMT) and extracellular matrix (ECM) production in organ fibrosis and associated diseases, such as vascular calcification. However, to the best of our knowledge, the role and underlying mechanism of action of Sox9 in renal fibrogenesis remains unknown. The results of the present study revealed that Sox9 expression levels were upregulated in the tubular epithelial cells of a rat model of obstructive nephropathy. Furthermore, the overexpression of Sox9 in NRK‑52E cells was discovered to promote renal tubular EMT and ECM aggregation, and these fibrogenic actions were potentiated by TGF‑β1. Notably, RNA‑sequencing analysis indicated the possible regulatory role of the PI3K/AKT signaling pathway in Sox9‑mediated renal tubular EMT and ECM aggregation. It was further demonstrated that the expression levels of phosphorylated AKT were upregulated in NRK‑52E cells overexpressing Sox9, while the PI3K inhibitors, LY29002 and wortmannin, inhibited the renal tubular EMT and ECM aggregation induced by the overexpression of Sox9 in NEK‑52E cells. In conclusion, the findings of the present study suggested that Sox9 may serve a profibrotic role in the development of renal tubular EMT and ECM aggregation via the PI3K/AKT signaling pathway. Therefore, Sox9 may be considered as a promising target for treating renal fibrosis."
  • p120-catenin regulates WNT signaling and EMT in the mouse embryo.[5] "epithelial mesenchymal transitions (EMTs) require a complete reorganization of cadherin-based cell-cell junctions. p120-catenin binds to the cytoplasmic juxtamembrane domain of classical cadherins and regulates their stability, suggesting that p120-catenin may play an important role in EMTs. Here, we describe the role of p120-catenin in mouse gastrulation, an EMT that can be imaged at cellular resolution and is accessible to genetic manipulation. Mouse embryos that lack all p120-catenin, or that lack p120-catenin in the embryo proper, survive to midgestation. However, mutants have specific defects in gastrulation, including a high rate of p53-dependent cell death, a bifurcation of the posterior axis, and defects in the migration of mesoderm; all are associated with abnormalities in the primitive streak, the site of the EMT. In embryonic day 7.5 (E7.5) mutants, the domain of expression of the streak marker Brachyury (T) expands more than 3-fold, from a narrow strip of posterior cells to encompass more than one-quarter of the embryo. After E7.5, the enlarged T+ domain splits in 2, separated by a mass of mesoderm cells. Brachyury is a direct target of canonical WNT signaling, and the domain of WNT response in p120-catenin mutant embryos, like the T domain, is first expanded, and then split, and high levels of nuclear β-catenin levels are present in the cells of the posterior embryo that are exposed to high levels of WNT ligand. The data suggest that p120-catenin stabilizes the membrane association of β-catenin, thereby preventing accumulation of nuclear β-catenin and excessive activation of the WNT pathway during EMT."
More recent papers  
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More? References | Discussion Page | Journal Searches | 2019 References | 2020 References

Search term: Epithelial Mesenchymal Transition | TWIST | ZEB | SNAIL

Older papers  
These papers originally appeared in the Some Recent Findings table, but as that list grew in length have now been shuffled down to this collapsible table.

See also the Discussion Page for other references listed by year and References on this current page.

  • Self-organization of a human organizer by combined Wnt and Nodal signalling[6] "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."
  • p53 coordinates cranial neural crest cell growth and epithelial-mesenchymal transition/delamination processes[7] "Neural crest development involves epithelial-mesenchymal transition (EMT), during which epithelial cells are converted into individual migratory cells. Notably, the same signaling pathways regulate EMT function during both development and tumor metastasis. p53 plays multiple roles in the prevention of tumor development; however, its precise roles during embryogenesis are less clear. We have investigated the role of p53 in early cranial neural crest (CNC) development in chick and mouse embryos. In the mouse, p53 knockout embryos displayed broad craniofacial defects in skeletal, neuronal and muscle tissues. In the chick, p53 is expressed in CNC progenitors and its expression decreases with their delamination from the neural tube. Stabilization of p53 protein using a pharmacological inhibitor of its negative regulator, MDM2, resulted in reduced SNAIL2 (SLUG) and ETS1 expression, fewer migrating CNC cells and in craniofacial defects."

Cell Junction Changes

Epithelial cells are connected by many different cell junctions, that mesenchymamal cells either lack or redistribute. Epithelial cell junctions include adherens junctions, desmosomes, gap junctions and tight junctions.

Mesenchymal cells interact with extracellular matrix and establish polarity in actin stress fibres and intermediate filament focal adhesions.

Epithelial or Mesenchymal Cell State[8]

Epithelial Mesenchymal Transition.jpg


Gastrulation

Links: gastrulation

Somite Development

The paraxial mesoderm segments to form somites The sclerotome component of each somite undergoes EMT grating away and eventually forming the axial skeletal elements of the Template:Vertebrae and ribs.


Note - the cartoons show just the embryo righthand side mesoderm development (the same events occur on the lefthand side).

Somite Links: 1 paraxial | 2 early somite | 3 sclerotome and dermomyotome | 4 dermatome and myotome | 5 somite spreading | SEM image - Human Embryo (week 4) showing somites | Movie - somitogenesis Hes expression

Cite this page: Hill, M.A. (2020, December 5) Embryology Developmental Mechanism - Epithelial Mesenchymal Transition. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Developmental_Mechanism_-_Epithelial_Mesenchymal_Transition

What Links Here?
© Dr Mark Hill 2020, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G
Links: somite

Neural Crest Development

Early neural crest cell development migration involves an initial epithelial mesenchymal transition to delaminate from the ectoderm neural tube layer.[9] A microRNA miR-203, acting as part of an epigenetic-microRNA regulatory network, appears influence the timing of this neural crest delamination.[10]


Links: neural crest

Heart Development

During heart development endocardial and epicardial cells produce non-cardiomyocyte lineages undergo rounds of epithelial to mesenchymal transition, see review.[11]


Links: Cardiovascular System Development

Palate Development

During the embryonic period the primary palate fusion, between maxillary process and the frontonasal prominence, requires loss of the epithelial seam.

Human Primary Palate
  • develops between embryonic stages 15 and 18.[12]
  • fusion in the human embryo between stage 17 and 18, from an epithelial seam to the mesenchymal bridge.
Stage17-18 Primary palate.gif
Links: palate

Respiratory Development

Neonatal Human Fetal Rabbit
Neonatal human pulmonary neuroendocrine cell EM01.jpg Fetal rabbit neuroepithelial body 01.jpg
Pulmonary neuroendocrine cell (EM)[13] Neuroepithelial body[13]

Pulmonary Neuroendocrine Cells (PNECs) differentiate in the airway epithelium in late embryonic to early fetal period.[14][15] Later in the mid-fetal period clusters of these cells form neuroepithelial bodies (NEBs). The cells migrate to to form these clusters by a process involving transient epithelial to mesenchymal transition. The process of migration has recently been described as “slithering”[16], where the cells transiently lose epithelial characteristics but remain associated with the membrane while traversing neighboring epithelial cells to reach cluster sites.


Links: Endocrine Respiratory | respiratory

Molecular

TWIST, ZEB, SNAIL

Twist

The twist family (TWIST1, TWIST2) of basic helix-loop-helix transcription factors are expressed in embryonic mesoderm and have been shown to be key regulators of the epithelial-mesenchymal transition. These transcription factors recognize a consensus DNA element called the E box. Mouse and human TWIST share 96.6% amino acid identity.


Links: TWIST1 | TWIST2

ZEB

The Zinc Finger E Box-Binding Homeobox (ZEB) family of 2-handed zinc finger/homeodomain proteins and functions as a DNA-binding transcriptional repressor that interacts with activated SMADs, the transducers of TGF-beta signaling.

Expression of ZEB1 in human epithelial cells can cause a morphologic change from an epithelial to a mesenchymal phenotype.[17]


Links: ZEB1 | ZEB2

Mesenchymal-to-Epithelial Transition

The alternate process involves the conversion of the embryonic connective tissue organization (mesenchyme) to an epithelial organization (epithelium) that can occur during developmental processes.

This process can be seen occurring during early somitogenesis.


It is also suggested that this mechanism occurs in the maternal uterus during endometrial regeneration following decidualization.[18][19]


Links: Mesenchymal Epithelial Transition

References

  1. Savagner P. (2010). The epithelial-mesenchymal transition (EMT) phenomenon. Ann. Oncol. , 21 Suppl 7, vii89-92. PMID: 20943648 DOI.
  2. Tseng CH, Murray KD, Jou MF, Hsu SM, Cheng HJ & Huang PH. (2011). Sema3E/plexin-D1 mediated epithelial-to-mesenchymal transition in ovarian endometrioid cancer. PLoS ONE , 6, e19396. PMID: 21559368 DOI.
  3. Hay ED. (1995). An overview of epithelio-mesenchymal transformation. Acta Anat (Basel) , 154, 8-20. PMID: 8714286
  4. Zhang Z, Wu W, Fang X, Lu M, Wu H, Gao C & Xia Z. (2020). Sox9 promotes renal tubular epithelial‑mesenchymal transition and extracellular matrix aggregation via the PI3K/AKT signaling pathway. Mol Med Rep , , . PMID: 32901875 DOI.
  5. Hernández-Martínez R, Ramkumar N & Anderson KV. (2019). p120-catenin regulates WNT signaling and EMT in the mouse embryo. Proc. Natl. Acad. Sci. U.S.A. , 116, 16872-16881. PMID: 31371508 DOI.
  6. 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.
  7. Rinon A, Molchadsky A, Nathan E, Yovel G, Rotter V, Sarig R & Tzahor E. (2011). p53 coordinates cranial neural crest cell growth and epithelial-mesenchymal transition/delamination processes. Development , 138, 1827-38. PMID: 21447558 DOI.
  8. Yang J, Antin P, Berx G, Blanpain C, Brabletz T, Bronner M, Campbell K, Cano A, Casanova J, Christofori G, Dedhar S, Derynck R, Ford HL, Fuxe J, García de Herreros A, Goodall GJ, Hadjantonakis AK, Huang RJY, Kalcheim C, Kalluri R, Kang Y, Khew-Goodall Y, Levine H, Liu J, Longmore GD, Mani SA, Massagué J, Mayor R, McClay D, Mostov KE, Newgreen DF, Nieto MA, Puisieux A, Runyan R, Savagner P, Stanger B, Stemmler MP, Takahashi Y, Takeichi M, Theveneau E, Thiery JP, Thompson EW, Weinberg RA, Williams ED, Xing J, Zhou BP & Sheng G. (2020). Guidelines and definitions for research on epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. , , . PMID: 32300252 DOI.
  9. Szabó A & Mayor R. (2018). Mechanisms of Neural Crest Migration. Annu. Rev. Genet. , 52, 43-63. PMID: 30476447 DOI.
  10. Sánchez-Vásquez E, Bronner ME & Strobl-Mazzulla PH. (2019). Epigenetic inactivation of miR-203 as a key step in neural crest epithelial-to-mesenchymal transition. Development , 146, . PMID: 30910825 DOI.
  11. von Gise A & Pu WT. (2012). Endocardial and epicardial epithelial to mesenchymal transitions in heart development and disease. Circ. Res. , 110, 1628-45. PMID: 22679138 DOI.
  12. Diewert VM & Lozanoff S. (1993). A morphometric analysis of human embryonic craniofacial growth in the median plane during primary palate formation. J. Craniofac. Genet. Dev. Biol. , 13, 147-61. PMID: 8227288
  13. 13.0 13.1 DiAugustine RP & Sonstegard KS. (1984). Neuroendocrinelike (small granule) epithelial cells of the lung. Environ. Health Perspect. , 55, 271-95. PMID: 6376101
  14. Cutz E. (1982). Neuroendocrine cells of the lung. An overview of morphologic characteristics and development. Exp. Lung Res. , 3, 185-208. PMID: 6188605
  15. Cutz E, Gillan JE & Bryan AC. (1985). Neuroendocrine cells in the developing human lung: morphologic and functional considerations. Pediatr. Pulmonol. , 1, S21-9. PMID: 3906540
  16. Kuo CS & Krasnow MA. (2015). Formation of a Neurosensory Organ by Epithelial Cell Slithering. Cell , 163, 394-405. PMID: 26435104 DOI.
  17. Vandewalle C, Comijn J, De Craene B, Vermassen P, Bruyneel E, Andersen H, Tulchinsky E, Van Roy F & Berx G. (2005). SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell-cell junctions. Nucleic Acids Res. , 33, 6566-78. PMID: 16314317 DOI.
  18. Cousins FL, Murray A, Esnal A, Gibson DA, Critchley HO & Saunders PT. (2014). Evidence from a mouse model that epithelial cell migration and mesenchymal-epithelial transition contribute to rapid restoration of uterine tissue integrity during menstruation. PLoS ONE , 9, e86378. PMID: 24466063 DOI.
  19. Patterson AL, Zhang L, Arango NA, Teixeira J & Pru JK. (2013). Mesenchymal-to-epithelial transition contributes to endometrial regeneration following natural and artificial decidualization. Stem Cells Dev. , 22, 964-74. PMID: 23216285 DOI.


Textbooks

Reviews

Wan Y, Liu H, Zhang M, Huang Z, Zhou H, Zhu Y, Tao Y, Xie N, Liu X, Hou J & Wang C. (2020). Prognostic value of epithelial-mesenchymal transition-inducing transcription factors in head and neck squamous cell carcinoma: A meta-analysis. Head Neck , 42, 1067-1076. PMID: 32048783 DOI.

Yang J, Antin P, Berx G, Blanpain C, Brabletz T, Bronner M, Campbell K, Cano A, Casanova J, Christofori G, Dedhar S, Derynck R, Ford HL, Fuxe J, García de Herreros A, Goodall GJ, Hadjantonakis AK, Huang RJY, Kalcheim C, Kalluri R, Kang Y, Khew-Goodall Y, Levine H, Liu J, Longmore GD, Mani SA, Massagué J, Mayor R, McClay D, Mostov KE, Newgreen DF, Nieto MA, Puisieux A, Runyan R, Savagner P, Stanger B, Stemmler MP, Takahashi Y, Takeichi M, Theveneau E, Thiery JP, Thompson EW, Weinberg RA, Williams ED, Xing J, Zhou BP & Sheng G. (2020). Guidelines and definitions for research on epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. , , . PMID: 32300252 DOI.

Thomson TM, Balcells C & Cascante M. (2019). Metabolic Plasticity and Epithelial-Mesenchymal Transition. J Clin Med , 8, . PMID: 31277295 DOI.

Lamouille S, Xu J & Derynck R. (2014). Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. , 15, 178-96. PMID: 24556840 DOI.

Botchkarev VA & Kishimoto J. (2003). Molecular control of epithelial-mesenchymal interactions during hair follicle cycling. J. Investig. Dermatol. Symp. Proc. , 8, 46-55. PMID: 12894994 DOI.

Articles

Zhang M, Wang Y, Matyunina LV, Akbar A & McDonald JF. (2020). The ability of miRNAs to induce mesenchymal-to-epithelial transition (MET) in cancer cells is highly dependent upon genetic background. Cancer Lett. , 480, 15-23. PMID: 32234315 DOI.

Hernández-Martínez R, Ramkumar N & Anderson KV. (2019). p120-catenin regulates WNT signaling and EMT in the mouse embryo. Proc. Natl. Acad. Sci. U.S.A. , 116, 16872-16881. PMID: 31371508 DOI.

Sánchez-Vásquez E, Bronner ME & Strobl-Mazzulla PH. (2019). Epigenetic inactivation of miR-203 as a key step in neural crest epithelial-to-mesenchymal transition. Development , 146, . PMID: 30910825 DOI.

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Mechanism Links: mitosis | cell migration | cell junctions |epithelial invagination | epithelial mesenchymal transition | mesenchymal epithelial transition | epithelial mesenchymal interaction | morphodynamics | tube formation | apoptosis | autophagy | axes formation | time | molecular

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Cite this page: Hill, M.A. (2020, December 5) Embryology Developmental Mechanism - Epithelial Mesenchymal Transition. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Developmental_Mechanism_-_Epithelial_Mesenchymal_Transition

What Links Here?
© Dr Mark Hill 2020, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G