The nucleus measures shape deformation for cellular proprioception and regulates adaptive morphodynamics

Abstract

The physical microenvironment regulates cell behavior during tissue development and homeostasis. How single cells decode information about their geometrical shape under mechanical 20 stress and physical space constraints within their local environment remains largely unknown. Here we show that the nucleus, the biggest cellular organelle, functions as a non-dissipative cellular shape deformation gauge that enables cells to continuously measure shape variations on the time scale of seconds. Inner nuclear membrane unfolding together with the relative spatial intracellular positioning of the nucleus provides physical information on the amplitude and type 25 of cellular shape deformation. This adaptively activates a calcium-dependent mechanotransduction pathway, controlling the level of 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 behaviour to their microenvironment. 30 One Sentence Summary: The nucleus functions as an active deformation sensor that enables cells to adapt their behavior to the tissue microenvironment.Main Text: The 3D shape of an organism is built by active force-generating processes at the cellular level and the spatio-temporal coordination of morphodynamic cell behavior. Contractility 35 of the acto-myosin cell cortex represents a major cellular force production mechanism underlying cellular shape change (1), cell polarization (2) and active cell migration dynamics (3). Contractility levels are regulated by the activity of non-muscle myosin II motor proteins (4) and are spatiotemporally controlled to tune single cell and tissue morphodynamics during development (5, 6) and tissue homeostasis and disease in the adult organism (7,8). Still, mechanisms that regulate the 40 set point level of cortical contractility on the single cell level remain poorly understood.

The nucleus acts as a ruler tailoring cell responses to spatial constraints

“…Relying on this ruler, cells can measure the degree of their environmental confinement and rapidly tailor specific behaviors to adapt to the confinement at time scales shorter than those associated with changes in gene expression. In the context of cell migration, such tailored cellular behaviors might help cells avoid environmental entrapment, which is relevant to cancer cell invasion, immune cell patrolling of peripheral tissues, and progenitor cell motility within a highly crowded cell mass of a developing embryo (33). The nuclear ruler mechanism defines an active function for the nucleus in cell migration, potentially explaining why enucleated cells show a poor motile capacity in dense collagen gels (34).…”

Emerin regulation of nuclear stiffness is required for fast amoeboid migration in confined environments

“…In contrast to the better known mechanisms of mechanotransduction in adherent cells (which often involve Src), cells may use different mechanisms for sensing confinement 31 . This idea is supported by recent evidence that the INM unfolds and activates a cytosolic Phospholipase A2 (cPLA2)-dependent mechanotransduction pathway in confined cells, increasing actomyosin contractility 12,13 .…”

“…Furthermore, this phenotypic transition has been found to be promoted by cell confinement 7,8,10,11 . Although compressing the cell (i.e., confinement) may be sufficient to pressurize the cytoplasm, recent studies have suggested that cells adapt to confinement by upregulating actomyosin contractility 12,13 . Because of this dependence on confinement, rapid LBBM is likely to require the precise tuning of cell stiffness.…”

On growth and force: mechanical forces in development

“…She then discussed the effect of cortical tension on cell differentiation, showing that a decrease in tension correlates with, and is required for, the differentiation of embryonic stem cells via ERK signalling (De Belly et al, 2019). Verena Ruprecht (CRG Barcelona, Spain), building on her earlier study of a confinement-induced amoeboid mode of migration in embryonic zebrafish cells (Ruprecht et al, 2015), reported important advances on the identification of the signaling pathway that controls the switch between different modes of cell motility through nucleus deformation, calcium release and a mechanosensitive nuclear phospholipase (Venturini et al, 2019). Ulrich Schwarz (Heidelberg University, Germany) discussed an intriguing aspect of malaria infection, whereby Plasmodium falciparum orchestrates a "re-engineering" of the red blood cell cytoskeleton, making the cells switch from their canonical biconcave shape to a spherical one, and covering them in thousands of protrusions rich in parasite-generated adhesion molecules.…”