Dynamics, nanoscale organization and modeling of LINC under mechanical stress – DynamoLINC

In response to mechanical cues, the cell nucleus regulates critical processes such as cell migration, cell fate, gene expression and cell differentiation. At the nuclear envelope, the Linker of Nucleoskeleton and Cytoskeleton (LINC) complexes serve as crucial mechanotransducing hubs. Yet, the nanoscale structural organization of LINC complexes and their functional coupling to the local mechanical states of the nuclear envelope are still enigmatic. Moreover, defective assembly of LINC components leads to abnormal nuclear mechanics which can induce severe diseases (such as Emery-Dreifuss muscular dystrophy (EDMD)) and premature ageing.
This proposal aims at : (i) establishing the nanoscale structural and molecular organizations of LINC proteins in human cells, in both normal and pathological contexts, (ii) using and developing novel optical force sensors to quantitatively define the architectural adaptability of LINC complexes in response to specific forces at the nuclear envelope, and (iii) providing predictive physical models of LINC complex functions as mechanotransducing hubs, via a close interplay of theory and experiments.
The project will be implemented through a highly multidisciplinary approach that integrates super-resolution and lifetime microscopy imaging, nanomanipulation, engineering of biomaterials to mechanically challenge cells, the development of novel optical force sensors for mechanobiology and theoretical modeling. It will generate fundamental insights into the mechanisms underlying normal nuclear functions and nuclear envelope disorders, which is of broad and immediate interest, and could, in the long-term, contribute novel rationales to develop therapies for patients affected by envelopathies.