Shaping The Nucleus, For Better Or Worse

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The nucleus is the cellular organelle that contains the genetic material. This compartment is surrounded by a double membrane known as the nuclear envelope, that allows the controlled exchange of material with the cytoplasm. The traditional view has been that the nuclear envelope is a passive barrier that mostly protects the genome and allows gene expression. However, we now know that under certain conditions, such as exposure to physical forces, cells can experience mechanical stress that deforms the nucleus. These deformations of the nuclear envelope can initiate signalling pathways that induce changes in gene expression and cellular behaviour. On the contrary, extreme deformations can lead to rupture of the nuclear envelope and genomic instability. We therefore need to know the relationship between nuclear deformations and cellular function. This project will answer this question by combining molecular and cell biology approaches with advanced quantitative microscopy and biophysics. We will build on our recent work identifying factors that regulate the shape of the nuclear envelope, thus allowing the selective perturbation of shape control. Specifically, we will elucidate i) what type of NE deformation constitutes a physiological signal or a pathological perturbation ii) the ultrastructure and dynamics of NE under stress iii) how NE deformations influence physiological functions such as the cellular adaptations to physical confinement and mechanical stress. This fundamental knowledge may inform new mechanisms of disease, from cardiopathies to cancer.