Mechanotransduction in development: a growing role for contractility

Abstract

Mechanotransduction research has focused historically on how externally applied forces can affect cell signalling and function. A growing body of evidence suggests that contractile forces that are generated internally by the actomyosin cytoskeleton are also important in regulating cell behaviour, and suggest a broader role for mechanotransduction in biology. Although the molecular basis for these cellular forces in mechanotransduction is being pursued in cell culture, researchers are also beginning to appreciate their contribution to in vivo developmental processes. Here, we examine the role for mechanical forces and contractility in regulating cell and tissue structure and function during development.

Figure 1. Forces that regulate Drosophila melanogaster dorsal closure

Shown is a diagram of a cross-section of a D. melanogaster embryo at the early stages of dorsal closure. The surface of the embryo (including the lateral epidermis and amnioserosa) is thought to be under tension throughout this stage, in part as a result of contractile activity of the cells within these tissues . The arrows represent movement of the tissue that results from these forces. Modified with permission from .

Figure 2. Cell shape regulates proliferation through the small GTPase RhoA

Restricting cell spreading decreases proliferation through the regulation of RhoA activity. RhoA promotes G1/S phase transition and cell proliferation through two pathways. First, the RhoA effector, ROCK, increases myosin light chain phosphorylation to generate cellular contractility. This generates tension in the cell, which is required for proliferation , . Second, the RhoA effector, mDia, activates Skp2 to inhibit p27kip. Since p27kip can no longer degrade the cyclin D1/cdk4 complex, the complex is free to phosphorylate Rb, leading to G1/S phase transition , . Because restricting cell shape decreases RhoA activity in some cell types, these two pathways are not activated. Without contractility and tension generation and Skp2 activity, G1/S phase transition is blocked and proliferation is reduced.

Figure 3. Mechanical regulation of Twist gene expression

The left panel shows a D. melanogaster embryo at the beginning of gastrulation, while the right panel shows the embryo during germband extension. During gastrulation, the tissue-lengthening movements that occur during germband extension push the tissue posteriorly, causing tissue and buckling (see black arrow). At the same time, the endoderm (shown in blue) invaginates (see blue arrow). This causes compression of the adjacernt stomodeal cells (shown in red). Inset: It is hypothesized that this compression (black arrows) leads to the Src42A-dependent nuclear translocation of the Armadillo transcription factor, which increases Twist expression , . This model places Twist expression in the appropriate location to regulate midgut differentiation. Modified with permission from .

Figure 4. Forces regulate the spatial organization of cells

A., During D. melanogaster oogenesis, border cell migration, follicle cells migrate down the midline of the egg chamber (blue cells are migrating cells, red cells denotes their final position). As cells are stretched or subjected to external force during migration, the tension generated causes the nuclear translocation of the SRF cofactor, MAL. Nuclear MAL and SRF can then regulate the expression of many genes, including genes required for cytoskeletal integrity. This model is proposed to allow cells to assemble and maintain a robust actin cytoskeleton during migration .B., The non-canonical Wnt pathway, also called the PCP (planar cell polarity) pathway, regulates many morphogenetic movements leading to cell and tissue spatial rearrangements during convergence and extension –. When Wnt binds to the Frizzled (Fz) receptor, this activated Dishevelled (Dsh), which then activates Daam1, leading to RhoA activation and ROCK-generated contractility and cellular tension.