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Molecular Biology

Mechanical Pressure as Gene Regulator

A central question in developmental biology is how non-genetic phenomena such as mechanical forces regulate growth. Here are the most recent findings on the role of such forces in the development of diametrically different tissues: human tumors, and plants.

For almost half a century, scientists believed that all the events that occured during the development of an organism were the sole product of what was written in its genes. The postulate began loosening up only a decade ago, as biologists started demonstrating that non-genetic phenomena also affected development.
In this context, researchers led by Emmanuel Farge1 at the Curie Institute in Paris have been studying the influence of mechanical pressure on genetic expression and cell proliferation during embryonic development, and more recently during tumor formation.
Working on embryos of fruit flies, the team first demonstrated that the forces generated by migrating cells during early embryonic development influence the expression of genes in neighboring cells. “The growing tissues and the genes responsible for the body's architecture are in close communication,” says Farge. “It's a sort of feedback loop indicating where genetic activation should be launched.” At the molecular level, they discovered that such mechanical pressure triggers the relocation, inside cells, of a protein called ß-catenin (involved in both cell adhesion and gene activation) from the external membrane to the nucleus, where it activates the transcription of developmental genes. This protein thus acts as a messenger transferring mechanical information to the genes.

gene regulator

© Jönsson & Krupinski, U. Lund, Suède

Modeling of the mechanical stress (white lines) induced by cell ablation in the epiderm of a plant meristem.

In humans, it is only during tumor formation that ß-catenin can be found inside the nucleus of adult cells. This phenomenon can occur when cells lack one or two copies of a gene called adenomatous polyposis coli (APC), whose physiological role includes clearing the excess of intra-cellular ß-catenin. APC mutations are known to pre-dispose to certain cancers such as colon cancer. When ß-catenin enters the nucleus, it activates the transcription of oncogenes–which are often identical to the developmental genes involved in embryogenesis. “This similarity is what led us to investigate whether mechanical forces might also come into play in the development of some cancers,” says Farge.
In recent experiments,2 the team applied controlled mechanical pressure on tissues of healthy mice colon cells, and on tissues of mice colon lacking one copy of the APC gene. Using fluorescence, they observed that pressure on healthy tissues did not induce the relocation of ß-catenin. However, in APC-deficient tissues, this protein did travel to the nucleus. “Mechanical pressure can thus contribute to the activation of oncogenes in cells genetically pre-disposed to cancer,” says Farge. “In these cells, one copy of the APC gene is not sufficient to counter the mechanically-induced ß-catenin relocalization.”
The team also noticed that the relocation occurred when the pressure applied equaled at least that of bowel movements inside the colon. “We still have to elucidate whether the pressure generated by bowel movements can initiate tumor genesis in APC deficient cells, or if pressure is only involved in the amplification process–cells of a growing tumor pressuring a pre-disposed neighboring cell, thereby feeding a chain reaction.”
On the other side of the realm of developmental biology, researchers have discovered the role of mechanical forces in plant development. An international team of researchers including CNRS scientists3 showed that the mechanical constraints generated by growing tissues determine the orientation of growth in neighboring cells.4 “Before that, we knew growing cells exert pressure on their neighbors, but we didn't know how this pressure was integrated as a message,” says lead author Olivier Hamant.
Working on tissues of plant meristem–a pool of undifferentiated cells found in zones where growth takes place–the team showed that intracellular components called microtubules react to external forces. Microtubules are known to control the direction of cell expansion. Using fluorescent live imaging, the team followed the organization of microtubules inside these tissues. In some cells, the microtubules appeared oriented in one direction. In other cells, they were disorganized. When the researchers applied different pressures on the tissue, they observed that the microtubules oriented themselves parallel to these forces, reorganizing themselves according to the maximum constraint. “This proves that mechanical constraints contribute to determining the direction of growth,” says Hamant.
The team now hopes to study the interactions between mechanical forces influencing direction and other parameters such as growth speed and genetic pre-disposition.

Clémentine Wallace

Notes :

1. Inserm UMR 168 (CNRS / Institut Curie / Inserm).
2. J. Whitehead et al., “Mechanical factors activate ß-catenin-dependent oncogene expression in APC1638N/+ mouse colon,” HFSP J., 2008. 2: 286.
3. Reproduction et développement des plantes (Université de Lyon / CNRS / ENS / INRA).
4. O. Hamant et al., “Developmental patterning by mechanical signals in arabidopsis,” Science, 2008. 322: 1650-5.

Contacts :

Emmanuel Farge
Institut Curie, Paris.
Olivier Hamant
ENS, Lyon.


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