Unlike in mathematics, the whole in biology is usually more than the sum of its single parts. This famous saying surely is true but sometimes the shape and the formation of tissues cannot only be expressed by the ensemble property of the respective cell type. Especially when new tissues are formed during gastrulation, mechanical properties of a small group of cells can change and be decisive for the development of the whole organism. Forces are beginning to
be considered important for this process [135]. The cell property responsible
for scaling the strain to an external or internal stress is elasticity or tension within the cell.
A variety of cellular processes that require a physical interaction of the cell with the surrounding environment are controlled by cell cortex tension.
These include cell migration [136,137,130,138], protrusion formation such as
cell surface blebbing [139], phagocytosis [140], tissue deformation like apical
constriction [133,131] and adhesion in general [118]. The origin for a cellular
cortex tension is an interplay between an outward-directed hydrostatic pressure
[141,142,143] and a net inward-directed myosin contractile force [136]. More
specialized functions are aided by other molecules. During cytokinesis for
example, tissue culture cells undergo dramatic cell shape changes and, while rounding up, produce significant forces. These forces are partially coordinated
Cortex tension drives many cell processes that include an in- teraction with the environment, such as migration, endocytosis and adhesion.
by the actin binding protein Moesin [144], an ERM member which couples
the cortical cytoskeleton to the plasma membrane (see Sec. 6.2). Cell shape
changes in general require generation of an intracellular force, which is then transmitted to the environment. At this interface, a dominant actin-cortex is assembled and resides in a pre-stressed state of higher potential energy which allows the cell to react quickly in response to intracellular regulation as well as extracellular signals. Such signals can be chemokines like SDF-1 which have been shown to induce extensive plasma-membrane blebbing upon modulation
of the actin cytoskeleton [130] during migration of zebrafish germ cells.
Cortex tension has a great influence on the shape of an interface of two or
more adhering cells [120, 127, 118]. Homophilic Cadherin adhesion tends to
globally flatten an interface between two adhering cells, thus creating a lower
local curvature in the adhering parts (see Fig.2.8A). Concomitantly it locally
sion reduces intercellular interfacial tension [118].The Cadherin-mediated con- tacts are stabilized intracellularly by α- and β-catenin which interact indirectly with actin cytoskeleton. On top of that, it has been shown that E-cadherin coordinates the assembly of different actin structures, such as belts and net-
works in the contact zone [145]. Therefore, adhesive interactions presumably
also modulate cortex tension of the interface by coordinating actin assemblies. Such assemblies, on the other hand, have been shown to modulate adhesion
[146, 147], presumably creating a feedback loop between adhesion and cortex
tension. Depending on the type of cell, different scenarios can happen (see Fig. 2.8).
1. When two cells adhere and a contractile acto-myosin network remains at the cell-cell boundary, it increases the cortical tension which reduces the contact surface. A higher tension impedes adhesion simply by forcing
Cortex tension is believed to counteract adhesion, e.g. a high tension impedes high adhesion and could result in repulsion
[148] the shapes into a sphere.
2. When adhesion overcomes the tension of the cortical network, the in- terface flattens and increases. Alternatively, engagement can cause the network to disassemble, therefore allowing an increase of the contact zone.
In other words, adhesion and cortex tension have opposite effects on the contact size between two cells and hence interfacial tension, because adhesion tends to maximize the contact, while cortex tension tries to minimize it (see Fig.
2.8A,B). The minimization effect can be easily explained by a maximization
of curvature, which would lead to point contact with infinite cortex tension. Similarly, with infinite adhesion, the two contacting bodies would collapse into a straight line, maximizing the interfacial contact between each other. There- fore, adhesion leads to a cell-cell contact increase which has to be balanced by cell cortex contractions. This scenario is well-explained in a recent model
[120] that describes the packing of cone cells in the Drosophila retina [127].
Simulations showed that when the interfacial tension of this system is only determined by adhesion, incorrect topologies are obtained. If the interfacial tension is modeled as a combination of adhesion and cortex tension, correct topologies and geometries are obtained which correctly explains the situation in-vivo.
Next to cell contact formation, cortex tension is one of the main driving
forces for plasma-membrane blebbing∗. Because the cortex is under isomet-
2.2. Adhesion and mechanics in development 33 Tccc Tcc Tcm Tcm c < = contraction contraction flow expansion retraction
membrane cytoskeleton linker proteins myosin motor proteins
cortical actin
membrane
A
C
B
Fig. 2.8 Cortex tension in the cell
A: Fluorescence micrograph of two cells injected with Alexa-546 coupled actin monomers. The actin-localization at the cell-cell interface determines the cortex tension at this boundary and together with adhesion the length of the contact zone. B: Cells in solution have a homogenous actin localization around the cortex. The acto-myosin cortex contracts leading to an inward- directed net force. When they come into contact, actin distribution at the cell-cell interface
determines the cortex tension and the shape of the doublet. A lower Tcc
c will lead to a larger
contact length with the same adhesion between the cells [118]. Blue arrows indicate the preferred
boundary behavior – expansion or retraction. C: Cell cortex tension influences blebbing activity. An isometric contraction of the cortex leads to an pressurized cytosol. Local cracks in the cortex or de-coupling of the membrane from the csk leads to a flow of cytosol into the spherical
protrusion. Subsequent actin re-polymerization in the bleb and myosin contraction will re-
incorporate the bleb into the cell body (after [149]).
ric contraction, the cytoplasm is believed to be under pressure (see Fig.2.8A
and Ref. [142, 143]). Once a critical hole size is reached due to breakage of
the cortical layer∗, cytoplasm flows into the region, creating a bulge which is
called membrane bleb. Without cortical tension, no protrusive activity would
be detectable [151], resulting in a complete retraction of cell surface blebs.
However, a tight regulation of cortex tension leads to localized blebbing activ-
ity [25] and can be used by the cell to break symmetry and to polarize [152] in
one direction. Such local changes of the tension in the cortical actin network can be achieved by either reducing the thickness of the acto-myosin belt, mod-
bing [150].
∗Either by locally increased contractility or decreased thickness of the cortex. Both can
ulating the activity of contractile elements or the degree of cross-linking [152]. It has been shown that tumor cells use this mechanism to migrate efficiently in 3D environment possibly without the use of specific cell surface adhesions. Herein, an increased activity of the Rho pathway resulted in a higher myosin
contraction and therefore multiple bleb nucleations [25]. Interestingly, the cor-
tex is in a state close to its critical tension and it has been calculated that a stress-increase of only 10% in the cortex leads to acto-myosin network damage
[152]. Therefore, cortex breakage seems to be an ‘easy’ way to polarize a com-
pletely symmetric, round cell. How this is achieved in-vivo is still unclear. A
Plasma-membrane blebbing is the outward ballooning of the membrane as its cytoskeletal at- tachments are weakened. The balloon is infiltrated by cytosol whose flow is powered by a iso- metric contraction of the cell cortex.
possible scenario would be a locally increased contraction after ligand binding to a certain cell receptor. Good candidates are G-protein coupled receptors
which cause a liberation of PIP2 to enhance myosin activity [153].
Cortical myosins have also been shown to guide protrusion formation in endothelial cell. During angiogenic sprouting, endothelial cells branch from existing vessels to invade the surrounding environment. This protrusion for- mation is preceded by a local depletion of myosin that promotes formation to
initiate angiogenesis [154]. Such a regulation of cortical stability suggests a
further function of myosin in maintaining cortex tension as an actin-filament cross-linker.
Despite the emphasis put on acto-myosin driven processes during devel- opment, it is important to note that cell adhesion is a fundamental property of all multicellular organisms and that no individual development would be possible without it. Cells need to adhere to form a tissue, and tissues build up the whole organism. Therefore a lot of developmental processes have been
shown to be governed by adhesion [16, 155, 19]. This is further underlined
by the appearance of approximately 5000 publications in the PubMed library when the term “cell + adhesion + morphogenesis” is applied. But what is cell adhesion and how is it maintained?