MRC National Institute for Medical Research, London
Science for Health
The battle to define embryonic territories
22 September 2011
In a collaboration with Angela Nieto's group in Alicante, Spain, scientists at NIMR have discovered that two transcription factors, Snail and Sox3, directly repress each other in a battle to decide which cells will undergo epithelial to mesenchyme transition. The research is published in Developmental Cell.
In the early embryos of birds and mammals, the epiblast comprises a sheet of pluripotent cells that will eventually give rise to all the cell types of the resulting embryo and animal. However, to do so, this single-cell layer has to be reorganised into a three-layered patterned structure comprising the three primary tissues of the embryo proper: the ectoderm, mesoderm, and endoderm. This is achieved by a process termed gastrulation, where epiblast cells change their properties at the posterior midline, giving rise to a structure called the primitive streak. Here the cells ingress and delaminate to form the mesoderm (the progenitors of the muscles, bone, kidneys, etc) and the endoderm (which will form the gut and organs such as the liver, pancreas and lungs) underneath the original layer. The cells that are left behind form the ectoderm, which gives rise to the central nervous system, sensory systems and the epidermis and associated tissues.
Much has been learned about the molecules and mechanisms that establish the anterior-posterior axis. This axis defines where the streak will form and determines and patterns the germ layers. It was known that a transcription factor called Snail is required for cells in the epiblast to change their properties from tightly adherent epithelial cells to loosely adherent and more migratory mesenchymal cells. However, this epithelial to mesenchymal transition (EMT) has to be carefully regulated in time and space to ensure that the correct number of cells ingress through the streak at the appropriate rate. If not, the germ layers will fail to form properly and tissue-interactions between them, which are required for subsequent patterning of the embryo, will be disrupted.
Robin Lovell-Badge, from NIMR's Division of Stem Cell Biology and Developmental Genetics, has collaborated with Angela Nieto's group in Alicante to show that an antagonistic relationship between Snail and SoxB1 transcription factors contributes to the subdivision of the epiblast into the two main territories – cells that will stay epithelial and form the ectoderm and those that will undergo EMT and enter the streak. The research made use of chick embryos, where it was found that Snail and Sox3 occupy non-overlapping domains, with the former occupying the position where the streak develops. Transfecting Snail into the Sox3 territory repressed the latter and led to EMT and to more cells entering the streak. Transfecting Sox3 into the Snail territory gave the reciprocal result. It was possible to show that the two genes directly repress each other’s transcription.
Using differentiating mouse embryonic stem cells deleted for Sox3 it was then demonstrated that the same situation was likely to take place in mammals; however, embryos mutant for Sox3 do not show a robust phenotype. Unlike the chick, in the mouse the related gene Sox2 is expressed prior to, and overlaps with, Sox3 in the epiblast. Sox2 and Sox3 proteins are very similar, suggesting functional redundancy, which was confirmed by looking at embryos null for Sox3 and heterozygous for Sox2, where gastrulation defects were now apparent. Apart from providing robust genetic evidence, this shows that the mechanisms for establishing these early embryonic territories, controlling which cells undergo EMT, and presumably the rate at which they do so, are likely to be conserved in amniotes.
Click image to view at full-size
Genetic data showing that reducing Sox2 and Sox3 gene copy numbers lead to an expansion of the Snail expression domain and to more cells undergoing EMT.
This work shows how cell behaviour can be dictated by the effects of transcription factors. In this case the fight between Snail and Sox factors determines whether or not EMT occurs. This is relevant to gastrulation but also, as shown in the paper, it is likely to be important for certain cancers, notably in the transition to a metastatic state.
Robin Lovell-Badge
Hervé Acloque, Oscar H. Ocaña, Ander Matheu, Karine Rizzoti, Clare Wise, Robin Lovell-Badge, M. Angela Nieto (2011).
Reciprocal repression between Sox3 and Snail transcription factors defines embryonic territories at gastrulation.
Developmental Cell 21, 546-58. Full text
See also
News categories
© MRC National Institute for Medical Research
The Ridgeway, Mill Hill, London NW7 1AA
Top of page