The nucleus acts as a ruler tailoring cell responses to spatial constraints
Preprint posted on December 05, 2019 https://www.biorxiv.org/content/10.1101/863514v1
The nucleus measures shape deformation for cellular proprioception and regulates adaptive morphodynamics
Preprint posted on December 05, 2019 https://www.biorxiv.org/content/10.1101/865949v1
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.
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?
- Charras, G., Sahai, E. Physical influences of the extracellular environment on cell migration. Nat Rev Mol Cell Biol15, 813–824 (2014)
- 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)
- 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
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