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

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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

INTRODUCTION

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.

RATIONALE

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.

RESULTS

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.

CONCLUSION

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.

Abstract

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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Science

Deep abiotic weathering of pyrite

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Getting rid of fool’s gold

Pyrite, also called fool’s gold, is an iron sulfide mineral that is very commonly found in rock but is almost nonexistent in sediments today. Pyrite oxidizes quickly and is a major source of sulfur to the ocean, but it is also a proxy for the oxygen content historically in Earth’s atmosphere. Gu et al. conducted a set of detailed observations of the pyrite oxidation process in a shale unit. The authors found that erosion tied to fracturing is just as important as the oxygen content for the dissolution process. They developed a model that helps determine the conditions in Earth’s past for which pyrite might have been stable and the role of microorganisms in the oxidation process.

Science, this issue p. eabb8092

Structured Abstract

INTRODUCTION

Oxidative weathering of pyrite, the most abundant sulfide mineral in Earth’s crust, is coupled to the biogeochemical cycles of sulfur, oxygen, carbon, and iron. Pyrite oxidation is key to these cycles because of its high reactivity with oxygen. Before the Great Oxidation Event (GOE), atmospheric oxygen concentrations were low on early Earth and pyrite was exposed at Earth’s surface, allowing erosion into sediments that were preserved in river deposits. Today, it oxidizes at depth in most rocks and is often not exposed at the land surface. To understand pyrite weathering through geologic time, researchers extrapolate the reaction kinetics based on studies from the laboratory or in acid mine drainage. Such work has emphasized the important role of microorganisms in catalyzing pyrite oxidation. But to interpret the oxidation rates of pyrite on early Earth requires knowledge of the rate-limiting step of the oxidation as it occurs naturally in rocks.

RATIONALE

We investigated the oxidation of pyrite in micrometer-sized grains, in centimeter-sized rock fragments, and in meter-scale boreholes at a small, well-studied catchment in a critical-zone observatory. Our goal was to determine the reaction mechanism of pyrite weathering in rocks as it occurs today. The slow-eroding catchment is underlain by shale, the most common rock type exposed on Earth. We determined weathering profiles of pyrite through chemical and microscopic analysis.

RESULTS

At the ridgelines of the shale watershed, most pyrite oxidation occurs within a 1-m-thick reaction zone ∼16 m below land surface, just above the depth of water table fluctuation. This is the reaction front at the borehole scale. Only limited oxidation occurs in halos around a few fractures at deeper depths. Above the depth where pyrite is 100% oxidized in all boreholes, rock fracture density and porosity are generally higher than below. However, the narrow parts of pore openings called pore throats remain small enough in oxidizing shale to limit access of microorganisms to the pyrite surface. During oxidation, iron oxides pseudomorphically replace the pyrite grains. High-resolution transmission electron microscopy (TEM) reveals that the oxidation front at grain scale is defined by a sharp interface between pyrite and an iron (oxyhydr)oxide (Fh) that is either ferrihydrite or feroxyhyte. This Fh then transforms into a banded structure of iron oxides that ultimately alter to goethite in outer layers. This complex oxidative transformation progresses inward from fractures when observed at clast scale.

CONCLUSION

Under today’s atmosphere, pyrite oxidation, rate-limited by diffusion of oxygen at the grain scale, is regulated by fracturing at clast scale. As pyrite is oxidized at borehole scale before reaching the land surface in most landscapes today, the oxidation rate is controlled by the movement of pyrite upward, which is in turn limited by the rate of erosion. Comparisons of shale landscapes with different erosion rates reveal that fracture spacing varies with erosion rate, so this suggests that fracture spacing may couple the landscape-scale to grain-scale rates. Microbial acceleration of oxidation globally today is unlikely in low-porosity rocks because pyrite oxidation usually occurs at depth, where pore throats limit access, as observed here for shales. Before the GOE, the rate of pyrite oxidation was instead controlled by the slower reaction kinetics in the presence of lower atmospheric oxygen concentrations. At that time, therefore, pyrite was exposed at the land surface, where microbial interaction could have accelerated the oxidation and acidified the landscape, as suggested by others. Our work highlights the importance of fracturing and erosion in addition to atmospheric oxygen as a control on the reactivity of this ubiquitous iron sulfide.

Schematic depiction of oxidative weathering of pyrite in rocks buried at meters depth.

Pyrite oxidation was studied from the molecular (TEM) scale of the pyrite―Fe oxide interface through clast and borehole scales to extrapolate to landscapes. The rate of oxidation of pyrite, limited at grain scale by oxygen diffusion through the shale matrix, is regulated at larger scales by fracturing and erosion.

Abstract

Pyrite is a ubiquitous iron sulfide mineral that is oxidized by trace oxygen. The mineral has been largely absent from global sediments since the rise in oxygen concentration in Earth’s early atmosphere. We analyzed weathering in shale, the most common rock exposed at Earth’s surface, with chemical and microscopic analysis. By looking across scales from 10−9 to 102 meters, we determined the factors that control pyrite oxidation. Under the atmosphere today, pyrite oxidation is rate-limited by diffusion of oxygen to the grain surface and regulated by large-scale erosion and clast-scale fracturing. We determined that neither iron- nor sulfur-oxidizing microorganisms control global pyrite weathering fluxes despite their ability to catalyze the reaction. This multiscale picture emphasizes that fracturing and erosion are as important as atmospheric oxygen in limiting pyrite reactivity over Earth’s history.

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Moving heart elements and cells

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Transposable elements comprise a large percentage of the human genome, with the endogenous retrovirus (ERV) subclass representing more than 8%. Using human pluripotent stem cell–derived cardiomyocytes and bioengineered micropatterning to recapitulate cardiogenesis, Wilson et al. found evidence that the primate-specific ERV MER41 is involved in primate heart development. A MER41-derived long noncoding RNA called BANCR is exclusively expressed in the fetal heart. When BANCR is eliminated, cardiomyocyte migration is disrupted. The cardiogenic transcription factor TBX5 and Hippo signaling factors TEAD4/YAP1 bind to a BANCR enhancer during fetal development. A related analysis in mouse shows that heart size increases with embryo BANCR knock-in.

Dev. Cell 54, 694 (2020).

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Obesity and inflammation

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Accumulation of fat cells (shown in yellow in this micrograph) may be promoted by gene variants linked to inflammation.

IMAGE: DAVID M. PHILLIPS/SCIENCE SOURCE

Obesity is associated with chronic inflammation, which can trigger other diseases such as atherosclerosis, type 2 diabetes, and even cancer. There appears to be a genetic component to excess fat accumulation, and studies suggest that inflammatory gene variants may contribute. Karunakaran et al. found that single-nucleotide polymorphisms in the human receptor-interacting serine/threonine-protein kinase 1 gene (RIPK1) increase its expression and are causally associated with obesity. RIPK1 is a key regulator of inflammatory responses and cell death. Silencing of Ripk1 in mice on a high-fat diet reduced fat mass, body weight, and inflammatory responses in adipose tissue. This suggests that RIPK1-mediated inflammation (and possibly other functions) contribute to obesity and that RIPK1 could be a therapeutic target.

Nat. Metab. 10.1038/s42255-020-00279-2 (2020).

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