PrefaceMechanotransduction research has focused historically on how externally applied forces can affect cell signalling and function. A growing body of evidence suggests that contractile forces generated internally by the actomyosin cytoskeleton are also important in regulating cell behaviour, and suggest a broader role for mechanotransduction in biology. While the molecular basis for these cellular forces in mechanotransduction are 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. IntroductionAlthough early conceptions of embryogenesis focused on the structural rearrangements that give rise to complex morphological body plans, as well as the mechanical origins of such rearrangements 1, 2 , much of our modern description of the process is presented in terms of spatiotemporally coordinated changes in gene expression patterning. Only recently have investigators begun to integrate these two approaches to provide early hints of a more global model that incorporates the contribution of mechanics to our modern molecular model of development.The early developmental stages from egg to a detailed body plan differ between species, but in general are often characterized by common structural rearrangements (Box 1). At the cellular level, one can describe many of these stereotypic events as emerging from the coordinated and iterative regulation of many basic cellular processes including proliferation, differentiation, and spatial rearrangements (Box 1). In addition to the indispensable functions of different genetic programs and soluble morphogens in regulating proliferation, differentiation, and physical rearrangements, these cellular processes are also regulated by mechanical forces. Much work has uncovered how mechanical forces are transduced into biochemical signals (mechanotransduction), and how mechanotransduction in turn impacts numerous cell functions 3 . In parallel, recent studies in vivo have also begun to characterize the forces that cells might experience during development.In this Review, we explore our nascent understanding of mechanical forces during embryogenesis and examine how these forces might regulate basic cellular processes (proliferation, differentiation, and organizational changes) specifically within the broader context of embryogenesis. For this reason, this review is not tailored to one specific species, but rather is written to be a general perspective. Drawing from both in vitro and in vivo studies from several model systems, we explore how actomyosin-mediated contractile forces regulate these cellular processes, and discuss how they might be mechanistically controlled during * Correspondence to C.S.C, chrischen@seas.upenn.edu. NIH Public Access Author ManuscriptNat Rev Mol Cell Biol. Author manuscript; available in PMC 2010 October 9. NIH-PA Author ManuscriptNIH-PA Author Manu...

Breast epithelial cells differentiate into tubules when cultured in floating three-dimensional (3D) collagen gels, but not when the cells are cultured in the same collagen matrix that is attached to the culture dish. These observations suggest that the biophysical properties of collagenous matrices regulate epithelial differentiation, but the mechanism by which this occurs is unknown. Tubulogenesis required the contraction of floating collagen gels through Rho and ROCK-mediated contractility. ROCK-mediated contractility diminished Rho activity in a floating 3D collagen gel, and corresponded to a loss of FAK phosphorylated at Y397 localized to 3D matrix adhesions. Increasing the density of floating 3D collagen gels also disrupted tubulogenesis, promoted FAK phosphorylation, and sustained high Rho activity. These data demonstrate the novel finding that breast epithelial cells sense the rigidity or density of their environment via ROCK-mediated contractility and a subsequent down-regulation of Rho and FAK function, which is necessary for breast epithelial tubulogenesis to occur.

Focal adhesions lie at the convergence of integrin adhesion, signaling and the actin cytoskeleton. Cells modify focal adhesions in response to changes in the molecular composition, two-dimensional (2D) vs. three-dimensional (3D) structure, and physical forces present in their extracellular matrix environment. We consider here how cells use focal adhesions to regulate signaling complexes and integrin function. Furthermore, we examine how this regulation controls complex cellular behaviors in response to matrices of diverse physical and biochemical properties. One event regulated by the physical structure of the ECM is phosphorylation of focal adhesion kinase (FAK) at Y397, which couples FAK to several signaling pathways that regulate cell proliferation, survival, migration, and invasion.

Matrix rigidity regulates a switch between TGF-β1–induced cell functions in two epithelial cell lines. On compliant polyacrylamide gels, TGF-β1 induced apoptosis, whereas on rigid gels, cells underwent an epithelial–mesenchymal transition (EMT). Compliant gels reduced PI3K/Akt activity, which was essential for cell survival and EMT on rigid gels.

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