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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

Too bright to breed

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Night light from coastal cities overpowers natural signals for coral spawning from neighboring reefs.

PHOTO: NOKURO/ALAMY STOCK PHOTO

Most coral species reproduce through broadcast spawning. For such a strategy to be successful, coordination has had to evolve such that gametes across clones are released simultaneously. Over millennia, lunar cycles have facilitated this coordination, but the recent development of bright artificial light has led to an overpowering of these natural signals. Ayalon et al. tested for the direct impact of different kinds of artificial light on different species of corals. The authors found that multiple lighting types, including cold and warm light-emitting diode (LED) lamps, led to loss of synchrony and spawning failure. Further, coastal maps of artificial lighting globally suggest that it threatens to interfere with coral reproduction worldwide and that the deployment of LED lights, the blue light of which penetrates deeper into the water column, is likely to make the situation even worse.

Curr. Biol. 10.1016/j.cub.2020.10.039 (2020).

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SpaceX launches Starlink app and provides pricing and service info to early beta testers

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SpaceX has debuted an official app for its Starlink satellite broadband internet service, for both iOS and Android devices. The Starlink app allows users to manage their connection – but to take part you’ll have to be part of the official beta program, and the initial public rollout of that is only just about to begin, according to emails SpaceX sent to potential beta testers this week.

The Starlink app provides guidance on how to install the Starlink receiver dish, as well as connection status (including signal quality), a device overview for seeing what’s connected to your network, and a speed test tool. It’s similar to other mobile apps for managing home wifi connections and routers. Meanwhile, the emails to potential testers that CNBC obtained detail what users can expect in terms of pricing, speeds and latency.

The initial Starlink public beta test is called the “Better than Nothing Beta Program,” SpaceX confirms in their app description, and will be rolled out across the U.S. and Canada before the end of the year – which matches up with earlier stated timelines. As per the name, SpaceX is hoping to set expectations for early customers, with speeds users can expect ranging from between 50Mb/s to 150Mb/s, and latency of 20ms to 40ms according to the customer emails, with some periods including no connectivity at all. Even with expectations set low, if those values prove accurate, it should be a big improvement for users in some hard-to-reach areas where service is currently costly, unreliable and operating at roughly dial-up equivalent speeds.

Image Credits: SpaceX

In terms of pricing, SpaceX says in the emails that the cost for participants in this beta program will be $99 per moth, plus a one-time cost of $499 initially to pay for the hardware, which includes the mounting kit and receiver dish, as well as a router with wifi networking capabilities.

The goal eventually is offer reliably, low-latency broadband that provides consistent connection by handing off connectivity between a large constellation of small satellites circling the globe in low Earth orbit. Already, SpaceX has nearly 1,000 of those launched, but it hopes to launch many thousands more before it reaches global coverage and offers general availability of its services.

SpaceX has already announced some initial commercial partnerships and pilot programs for Starlink, too, including a team-up with Microsoft to connect that company’s mobile Azure data centers, and a project with an East Texas school board to connect the local community.

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Erratum for the Report “Meta-analysis reveals declines in terrestrial but increases in freshwater insect abundances” by R. Van Klink, D. E. Bowler, K. B. Gongalsky, A. B. Swengel, A. Gentile, J. M. Chase

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S. Rennie, J. Adamson, R. Anderson, C. Andrews, J. Bater, N. Bayfield, K. Beaton, D. Beaumont, S. Benham, V. Bowmaker, C. Britt, R. Brooker, D. Brooks, J. Brunt, G. Common, R. Cooper, S. Corbett, N. Critchley, P. Dennis, J. Dick, B. Dodd, N. Dodd, N. Donovan, J. Easter, M. Flexen, A. Gardiner, D. Hamilton, P. Hargreaves, M. Hatton-Ellis, M. Howe, J. Kahl, M. Lane, S. Langan, D. Lloyd, B. McCarney, Y. McElarney, C. McKenna, S. McMillan, F. Milne, L. Milne, M. Morecroft, M. Murphy, A. Nelson, H. Nicholson, D. Pallett, D. Parry, I. Pearce, G. Pozsgai, A. Riley, R. Rose, S. Schafer, T. Scott, L. Sherrin, C. Shortall, R. Smith, P. Smith, R. Tait, C. Taylor, M. Taylor, M. Thurlow, A. Turner, K. Tyson, H. Watson, M. Whittaker, I. Woiwod, C. Wood, UK Environmental Change Network (ECN) Moth Data: 1992-2015, NERC Environmental Information Data Centre (2018); .

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