Nuclear shape, mechanics, and mechanotransduction

Abstract

In eukaryotic cells, the nucleus contains the genome and is the site of transcriptional regulation. The nucleus is the largest and stiffest organelle and is exposed to mechanical forces transmitted through the cytoskeleton from outside the cell and from force generation within the cell. Here, we discuss the effect of intra- and extracellular forces on nuclear shape and structure and how these force-induced changes could be implicated in nuclear mechanotransduction, ie, force-induced changes in cell signaling and gene transcription. We review mechanical studies of the nucleus and nuclear structural proteins, such as lamins. Dramatic changes in nuclear shape, organization, and stiffness are seen in cells where lamin proteins are mutated or absent, as in genetically engineered mice, RNA interference studies, or human disease. We examine the different mechanical pathways from the force-responsive cytoskeleton to the nucleus. We also highlight studies that link changes in nuclear shape with cell function during developmental, physiological, and pathological modifications. Together, these studies suggest that the nucleus itself may play an important role in the response of the cell to force.

Figure 1. Pathways of force transmission from the extracellular matrix to the nucleus

External forces can act on the cell through substrate strain or fluid shear stress. Integrins and other adhesion molecules physically couple the actin cytoskeleton to the extracellular matrix and can respond to extracellular ligands and intracellular signals. Cytoskeletal cross-linkers such as plectin can interconnect actin filaments, intermediate filaments, and microtubules. Plectin can also directly bind to nesprin-3 on the outer nuclear membrane, while the giant isoforms of nesprin-1 and -2 contain N-terminal actin binding domains. At the nuclear envelope, nesprins interact through their C-terminal KASH domain with SUN proteins, which cross the perinuclear space. At the inner nuclear membrane, SUN proteins can bind to lamins and other nuclear envelope proteins, which in turn can bind to DNA and chromatin, completing the physical link between the nucleus and the cytoskeleton. Cellular components are not drawn to scale.