Research Article

The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior

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Science  16 Oct 2020:
Vol. 370, Issue 6514, eaba2644
DOI: 10.1126/science.aba2644

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The nucleus makes the rules

Single cells continuously experience and react to mechanical challenges in three-dimensional tissues. Spatial constraints in dense tissues, physical activity, and injury all impose changes in cell shape. How cells can measure shape deformations to ensure correct tissue development and homeostasis remains largely unknown (see the Perspective by Shen and Niethammer). Working independently, Venturini et al. and Lomakin et al. now show that the nucleus can act as an intracellular ruler to measure cellular shape variations. The nuclear envelope provides a gauge of cell deformation and activates a mechanotransduction pathway that controls actomyosin contractility and migration plasticity. The cell nucleus thereby allows cells to adapt their behavior to the local tissue microenvironment.

Science, this issue p. eaba2644, p. eaba2894; see also p. 295

Structured Abstract


Human beings are equipped with multiple senses (sight, hearing, smell, taste, touch, and proprioception) to help them to react properly to their environment. The human body is composed of trillions of cells that similarly require multiple sensations to fulfill their task in specific tissues. From a cellular perspective, the three-dimensional (3D) tissue microenvironment is a crowded place in which cells experience a multitude of physical constraints and mechanical forces. These conditions can lead to cell shape changes—for example, as observed when motile cells squeeze through tight spaces or when cells deform in densely packed tissue regions. To guarantee tissue integrity and homeostasis, cells need to be able to respond to these mechanical challenges in their tissue microenvironment, both in the adult organism and during embryonic development. How cells can measure their own shape and adapt their dynamic behavior to the physical surroundings remains an open question.


The actomyosin cytoskeleton is a structural scaffold within cells that controls mechanical cell properties and dynamic cellular processes such as cell migration. Cytoskeletal networks can contract and thereby generate force by using the activity of myosin II motor proteins. Cell contractility influences the mode and speed of cell migration. Various cell types have been observed to switch to a highly contractile and fast amoeboid cell migration type in constrained environments. This suggests the presence of a conserved mechanosensitive pathway capable of translating mechanical cell deformations into adaptive cytoskeletal arrangements that allow cells to react dynamically to changes in their tissue microenvironment.


Here, we show that the nucleus, the biggest organelle in the cell, translates cell shape changes into a deformation signal regulating cell behavior. We found that variable cell squeezing defines the specific set point of cell contractility, with increased cell deformation leading to higher cortical myosin II levels and promoting fast amoeboid cell migration. This adaptive cellular response to deformation was rapid (<1 min), stable over time (>60 min), and reversible upon confinement release. We found that changes in cell behavior were associated with nucleus stretch and unfolding of the inner nuclear membrane (INM), supporting the idea that the nucleus functions as a fast mechanical responder for sensing cell shape variations. We show that INM unfolding triggered a calcium-dependent mechanotransduction pathway via the activation of cytosolic phospholipase A2 (cPLA2) and metabolite production of arachidonic acid (AA) that regulates myosin II activity. This establishes the nucleus as an intracellular mechano-gauge that measures shape deformations and directly controls morphodynamic cell behavior. Furthermore, we found that the combination of nuclear deformation and intracellular calcium levels, regulated by nuclear positioning, allows cells to distinguish distinct shape deformations and adapt their behavior to changing tissue microenvironments.


Here, we show that the nucleus acts as a central hub for cellular proprioception, which, in a manner similar to how we sense our body posture and movement, enables single cells to precisely interpret and respond to changes in their 3D shape. The rapid increase in cell contractility and migration competence upon cell squeezing equips cells with a rapid “evasion reflex”: In constrained environments, cells polarize and acquire a rapid migratory phenotype that enables cells to move away and squeeze out from tight spaces or crowded tissue regions. The nucleus thus allows cells to decode changes in their shape and to adjust their behavior to variable tissue niches, relevant for healthy and pathological conditions.

The nucleus acts as an elastic mechanotransducer of cellular shape deformation and controls dynamic behavior.

Cell shape changes induce inner nuclear membrane unfolding and activation of the cPLA2-AA pathway. This transduces mechanical nucleus stretch into myosin II recruitment to the cell cortex regulating actin cytoskeleton contractility and cellular behavior. High contractility levels further lead to motile cell transformation and initiate amoeboid cell migration.


The physical microenvironment regulates cell behavior during tissue development and homeostasis. How single cells decode information about their geometrical shape under mechanical stress and physical space constraints within tissues remains largely unknown. Here, using a zebrafish model, we show that the nucleus, the biggest cellular organelle, functions as an elastic deformation gauge that enables cells to measure cell shape deformations. Inner nuclear membrane unfolding upon nucleus stretching provides physical information on cellular shape changes and adaptively activates a calcium-dependent mechanotransduction pathway, controlling actomyosin contractility and migration plasticity. Our data support that the nucleus establishes a functional module for cellular proprioception that enables cells to sense shape variations for adapting cellular behavior to their microenvironment.

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