Role of Lamin A/C in nuclear mechanics and mechanotransduction

Luv Srivastava

The cell and nucleus have existed in eukaryotic life for billions of years, with the nucleus first being described by Robert Brown in 1831. The nucleus is the largest organelle inside the cell and is the master controller of cell function. The nucleus houses other important cellular components having essential roles in different cellular processes. 

While diverse cellular components have been identified as mechanotransduction elements, the deformation of the nucleus itself is a critical mechanosensory mechanism, implying that nuclear stiffness is essential in determining responses to intracellular and extracellular stresses. The nuclear membrane protein, lamin A/C, is known to be an important contributor to nuclear stiffening, but bulk moduli of nuclei have not been reported for various levels of lamin A/C. Here we measure the nuclear bulk moduli as a function of lamin A/C expression and applied osmotic stress, revealing a linear dependence. The bulk moduli can be calculated using the change in volume and the osmotic pressure applied using the formula B= V (dP/dV) and was found to fall in the range of 2-4 Mega Pascal (MPa).

We also find that the nuclear compression is anisotropic, with the vertical axis of the nucleus being more compliant than the minor and major axes in the substrate plane. Further we observed the distribution of lamin A/C to be heterogenous along the nuclear envelope. We then related the spatial distribution of lamin A/C with sub-micron 3D nuclear envelope deformation, revealing that local areas of the nuclear envelope with higher density of lamin A/C have correspondingly lower local deformations. These findings describe the complex dispersion of nuclear deformations as a function of lamin A/C expression and distribution, implicating a lamin A/C role in mechanotransduction. 

While observing the nuclear deformation of the nuclei, we found an interesting variation in the way a wild type nucleus and a progeria nucleus deform. To further explore the mechanical differences in the way nuclei compress, we are focussing on the orientation and movement of lamin or progerin fibres, respectively.

Srivastava, LK et al. “Spatial distribution of lamin A/C determines nuclear stiffness and stress-mediated deformation”, J Cell Sci, 134(10):jcs248559, 2021

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Department of Bioengineering

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