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When mechanical stress alters developmental gene expression

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17.09.2003

In the fly embryo, the Twist gene is normally expressed only in the ventral region (above)
When rhe embryo is pressed between two slides (below) in the dorsal region.

In this and the following plate, Twist proteins and ß catenin are labeled with a fluorescent green protein


The pressure of the embryo perturbs the localization of ß catenin, a protein which ensures cohesion between cells within tissues.
When mechanical pressure is applied to the embryo, ß catenin enters the cell nucleus (on right), whereas to perform its role as an "adhesive" between cells it must be on the cell surface.

During its growth, an embryo changes shape under the control of the so-called developmental genes. Emmanuel Farge, a researcher at the Institut Curie, lecturer at the Paris VII University, and member of the Institut Universitaire de France, has just shown that mechanical pressure applied to a fly embryo influences the expression of its developmental genes. So not everything is purely genetic and some features of the living cell are also mechano-sensitive.

It remains to be seen whether this phenomenon also applies to human tissues. And could the growth of a tumor that compresses tissues play a role in gene deregulation?
These results published in the 19 August issue of Current Biology are likely to change the way geneticists think.

The life of all living organisms starts from a single cell. Each cell subsequently undergoes changes enabling it to find its place and assume its role. The cells have the same genetic make-up but follow different routes and fulfill distinct activities: they differentiate. To achieve this they activate or suppress the production of specific proteins. What are the signals that determine the function of cells? How does a cell become a building block in the stomach or in the brain?

For almost 50 years biologists thought that everything was written in the genes. And then along came epigenetics¹. Ever since it seems to have been agreed that chemical modifications occurring around the DNA molecule can lead to changes on the scale of the organism.

Epigenetic processes even appear to impose the switching on and off of a gene. In a word, epigenetics underpins the programming of cells. These new theories clearly undermined the dogma of "everything is genetic", and now Emmanuel Farge at the Institut Curie has weakened it even further.

There are not only genes…

An embryo has a particular shape at each stage of its development. These successive deformations exert mechanical pressures on the embryo. Yet is this their only consequence? Can they influence, even regulate, the expression of developmental genes?

This is the question posed by Emmanuel Farge², in his studies of embryonic development of Drosophila, the fruit fly so prized by biologists.

Emmanuel Farge is interested in the Twist gene, which is essential for embryonic development in Drosophila (see box below) and whose human equivalent is involved in the development of certain cancers.

This gene is normally expressed only in cells located ventrally in the embryo. But on applying mechanical pressure to the Drosophila embryo, Emmanuel Farge noted that the Twist gene was then expressed in all the embryo’s cells. Although fleeting, this activation has important consequences since it blocks embryonic development.

It therefore seems that mechanical pressure exerted on the embryo perturbs essential cellular processes. Emmanuel Farge has shown that one of the pathways affected is that of b catenin, a protein whose function is two-fold: it acts both as an anchor ensuring cohesion between cells in tissues and as a transcription factor which can stimulate the expression of certain genes. b catenin could be the link between mechanical pressure and genes.

According to Emmanuel Farge, during normal embryonic development the formation of one of the intermediate layers, the mesoderm, exerts pressure on the anterior region of the embryo and so leads to the expression of the Twist gene. Significantly, the Twist gene is not expressed in mutant embryos in which this mechanical pressure is absent.

This is the first time that a mechanical constraint has been shown to influence the genetic control of the development of Drosophila embryo. Genes are therefore not alone in influencing development. Henceforth it will be necessary to take into account the mechanical sensitivity of living cells.

This discovery in the development of the Drosophila embryo opens up new fields of research and raises numerous questions:

Can other genes be influenced? What of human tissues? Could such pressures, caused, for example, by a tumor mass, perturb the expression of certain genes?

Reference

"Mechanical Induction of Twist in the Drosophila Foregut/Stomodeal Primordium"
Emmanuel Farge
Current biology (www.current-biology.com), vol 13, pp 1365-1377, 19 August 2003
1Institut Universitaire de France, Université Paris VII, Mechanics and Genetics of Developmental Embryogenesis Group, UMR 168 CNRS/Institut Curie.

Notes

¹ Epigenetics covers all biological phenomena not strictly determined by the genetic material. Epigenetic variations affect the organism’s phenotype without altering its genotype.
² Associate Professor at the Paris VII University, biologist and physicist in the research unit UMR 168 CNRS/Institut Curie Physical Chemistry "Curie" headed by Jean-François Joanny.


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Twist, development gene
In Drosophila, the Twist gene is indispensable from a very early stage in embryonic development. It participates in the formation and positioning of cells which, notably, give rise to muscle tissue. When the Twist gene is inactivated in an embryo, there is no further formation of mesoderm, of internal organs or of muscles: the ’embryo is twisted in its envelope. The Twist gene is a transcription factor, i.e. it directly controls the expression of other genes.
The human equivalent of this gene, which bears the same name, is known to be involved in the development of certain cancers. It appears to play a part in the pathways implicated in programmed cell death, or apoptosis, which is defective in cancer cells.

Catherine Goupillon | Source: Institut Curie
Further information: www.curie.fr

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