Menu

Close

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

A.J. Lomakin, C.J. Cattin, D. Cuvelier, Z. Alraies, M. Molina, G. Nader, N. Srivastava, J.M. Garcia-Arcos, I.Y. Zhitnyak, A. Bhargava, M.K. Driscoll, E.S. Welf, R. Fiolka, R.J. Petrie, N. Manel, A.M. Lennon-Duménil, D.J. Müller, M. Piel

Preprint posted on December 05, 2019 https://www.biorxiv.org/content/10.1101/863514v1

and

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

Valeria Venturini, Fabio Pezzano, Frederic Català Castro, Hanna-Maria Häkkinen, Senda Jiménez-Delgado, Mariona Colomer-Rosell, Mónica Marro Sánchez, Queralt Tolosa-Ramon, Sonia Paz-López, Miguel A. Valverde, Pablo Loza-Alvarez, Michael Krieg, Stefan Wieser, Verena Ruprecht

Preprint posted on December 05, 2019 https://www.biorxiv.org/content/10.1101/865949v1

Can cells measure up? The nucleus acts as a cellular ruler during migration through 3D environments

Selected by Nicola Stevenson

Categories: cell biology

Importance

The ability to migrate is an intrinsic property of animal cells which is essential for a very diverse array of developmental and physiological processes. The mechanisms of migration are also quite diverse and depend on both the biochemical state of the cell itself and the properties of the environment through which it must progress1. All modes of motility however are reliant on the actomyosin cytoskeleton. In this dynamic structure, F actin polymers are assembled inside the cell to provide an intracellular scaffold on which myosin motors can assemble. Upon receiving a signal, the myosin motors then pull two bound actin filaments relative to each other causing the structure to either contract or extend. This drives cell shape changes and force generation to co-ordinate migration2.

As cells migrate through tissues, they must navigate the spaces created by the extracellular matrix which has variable spatial and biophysical properties. Often cells will encounter small spaces in an unyielding, stiff matrix which must be traversed. They are then faced with a choice – to squeeze through or to proteolytically digest their way past. In order to make these decisions and to adjust behaviour accordingly, cells must be able to sense how these constrictions relate to their size, but, to date, no one has been able to demonstrate this level of proprioception in cells.

In the two papers presented here, both Lomakin et al and Venturini et al address this problem by producing a series of thoroughly executed experiments demonstrating that the nucleus is capable of acting as a cellular ruler.

Key findings

Using different cell types and complimentary approaches, each study independently establishes that cell constriction below a certain size, which roughly corresponds to the size of the nucleus, induces a reversible recruitment of myosin-II to the cell cortex. This is followed by contraction of the actin cytoskeleton and non-apoptotic cell blebbing. Such behaviour is reminiscent of amoeboid migration and indeed Lomakin et al shows that it seems to promote acceleration through small holes in a 3D environment.

In trying to identify the mechanism of mechano-transduction under these conditions, the authors focus on the nucleus. Measurements of nuclear spatial parameters at rest and under confinement revealed that whilst the nuclear volume does not change with cell constriction, the surface area increases significantly. Specifically, wrinkles and ruffles in the nuclear envelope unfold as the cell is confined until the membrane is under tension. This unfolding temporally precedes cortical myosin II recruitment suggesting membrane tension may initiate the contractile response.

One key player identified in this process in both studies was the phospholipase cPLA2, which detects lipid packing and is activated when the nucleus is stretched3. When cPLA2 function or nuclear recruitment was inhibited, cells failed to generate a contractile response. Furthermore, cPLA2 was recruited to the nuclear envelope specifically at the cell confinement threshold for actomyosin contractility. The primary product of cPLA2 activity, arachidonic acid, was also observed primarily in confined cells.

Intracellular calcium was similarly found to be essential for this process. Indeed, Venturini et al present data suggesting that nuclear unfolding is not sufficient to induce a contractile response without calcium release at points of ER compression between the unfolded nucleus and plasma membrane. Thus, calcium and nuclear deformation work in concert to respond to specific cell shape changes.

In conclusion, confinement of cell height causes the nuclear envelope to unfold in order to maintain nuclear volume. When cell confinement and nuclear unfolding reaches a threshold at which the nuclear membrane is under tension and the ER sufficiently compressed, intracellular calcium is released and cPLA2 recruited to the nuclear envelope. Active cPLA2 produces arachidonic acid and this acts as a second messenger along with calcium to coordinate a contractile response.

Why I chose this paper

I chose these papers because of the great way in which they provide a comprehensive story that goes a long way to answering long held questions about how cells relate their size to environmental constrictions. It will be interesting to see how broadly this mechanism is utilised in different in vivo settings as the research progresses and what the determinants are for this mode of transport.

Questions for authors

You have demonstrated that this pathway is activated in a 3D environment but the majority of your experiments appear to specifically involve height compression – how do you think the confinement pressures in the experimental set up relate to those encountered when migrating forwards through a 3D hole?

Have you looked at what other cytoskeletal elements do at this level of confinement?

Your experiments show polarisation of cells in response to confinement but how do you think they generate directionality to get through the hole? Does this pathway link to others such as regulation of chemotaxis?

If cells are able to sense a confinement threshold at which to adopt an amoeboid migration strategy and accelerate, do you believe there could be a mechanism to reverse the direction of migration if the cell is being pulled in a hole that is too small?

References

  1. Charras, G., Sahai, E. Physical influences of the extracellular environment on cell migration. Nat Rev Mol Cell Biol15, 813–824 (2014)
  2. Murrell, M., Oakes, P., Lenz, M. et al.Forcing cells into shape: the mechanics of actomyosin contractility. Nat Rev Mol Cell Biol 16, 486–498 (2015)
  3. Enyedi, B. Jelcic, M. Niethammer, P. The cell nucleus serves as a mechanotransducer of tissue damage-induced Cell 165 1160-1170.

 

Posted on: 4th February 2020 , updated on: 5th February 2020

doi: https://doi.org/10.1242/prelights.16721

(3 votes)




  • Have your say

    Your email address will not be published. Required fields are marked *

    This site uses Akismet to reduce spam. Learn how your comment data is processed.

    Sign up to customise the site to your preferences and to receive alerts

    Register here

    preLists in the cell biology category:

    3D Gastruloids

    A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells)

     



    List by Paul Gerald L. Sanchez and Stefano Vianello

    ECFG15 – Fungal biology

    Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome

     



    List by Hiral Shah

    ASCB EMBO Annual Meeting 2019

    A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

     



    List by Madhuja Samaddar, Ramona Jühlen, Amanda Haage, Laura McCormick, Maiko Kitaoka

    EMBL Seeing is Believing – Imaging the Molecular Processes of Life

    Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

     



    List by Gautam Dey

    Autophagy

    Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.

     



    List by Sandra Malmgren Hill

    Lung Disease and Regeneration

    This preprint list compiles highlights from the field of lung biology.

     



    List by Rob Hynds

    Cellular metabolism

    A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.

     



    List by Pablo Ranea Robles

    BSCB/BSDB Annual Meeting 2019

    Preprints presented at the BSCB/BSDB Annual Meeting 2019

     



    List by Gautam Dey

    MitoList

    This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.

     



    List by Sandra Franco Iborra

    Biophysical Society Annual Meeting 2019

    Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA

     



    List by Joseph Jose Thottacherry

    ASCB/EMBO Annual Meeting 2018

    This list relates to preprints that were discussed at the recent ASCB conference.

     



    List by Gautam Dey, Amanda Haage
    Close