Mechanical control of cell migration and proliferation by Adherens Junctions and the LINC complex – MELINCAD

In multicellular organisms, tissue morphogenesis is thought to result from the combined influence of the genetic program and environmental cues on cell behaviors. As embryonic development proceeds, cell migration and proliferation are essential for tissue growth and remodeling. Migrating and proliferating cells generate and experience mechanical forces that are propagated throughout the organism. Ultimately, these forces may regulate genetic programs by activating transcription factors. Mechanical forces increasingly appear as critical determinants of tissue morphogenesis. However, the macromolecular structures bearing mechanical forces in, and between cells, are mostly unknown. So are their functions in the regulation of cell migration and proliferation.
In an epithelium, cells adhere to one another through Adherens Junctions linked to the cytoskeleton. The cytoskeleton is also linked to the nucleus through the LINC complex. Both Adherens Junctions and LINC complexes are involved in cell migration and associate with beta-catenin, a major transcription factor involved in cell proliferation. Interestingly, beta-catenin regulation of proliferation is dependent on mechanical signals during epithelial morphogenesis. Therefore, Adherens Junctions and LINC complexes may together be involved in the mechanical co-regulation of cell migration and beta-catenin-dependent genetic programs.
However, the molecular mechanisms that regulate mechanotransduction through the Adherens Junctions and LINC complexes are poorly understood. So is whether these complexes are involved in the same pathway.
To investigate the mechanotransduction properties of these complexes and their relationships, I will leverage an original methodology, the Molecular Tension Microscopy, that allows mechanical tension measurement with molecular specificity in live cells. I will characterize key molecular mechanisms of Adherens Junctions and LINC complexes mechanotransduction, and determine whether adhesions and LINC complexes are involved in a same mechanotransduction pathway that co-regulates cell migration and proliferation during epithelial morphogenesis. This will deepen our insights in a fundamental aspect of multicellular development: the interplay between genetic programs and tissue mechanics during morphogenesis.
Dysfunctions of the Adherens Junctions and LINC complexes are associated with cancer metastasis, in which cells exhibit profoundly altered migration and proliferation features. Moreover, dysfunction of the LINC complex is also involved in an array of genetic diseases such as myopathies, lipodystrophies or progeria. Thus, increased knowledge of their mechanotransduction mechanisms may offer novel diagnostic or therapeutic perspectives.