Modeling the roles of cohesotaxis, cell-intercalation, and tissue geometry in collective cell migration of Xenopus mesendoderm.

Collectively migrating Xenopus mesendoderm cells are arranged into leader and follower rows with distinct adhesive properties and protrusive behaviors. In vivo, leading row mesendoderm cells extend polarized protrusions and migrate along a fibronectin matrix assembled by blastocoel roof cells. Traction stresses generated at the leading row result in the pulling forward of attached follower row cells. Mesendoderm explants removed from embryos provide an experimentally tractable system for characterizing collective cell movements and behaviors, yet the cellular mechanisms responsible for this mode of migration remain elusive. We introduce an agent-based computational model of migrating mesendoderm in the Cellular-Potts computational framework to investigate the relative contributions of multiple parameters specific to the behaviors of leader and follower row cells. Sensitivity analyses identify cohesotaxis, tissue geometry, and cell intercalation as key parameters affecting the migration velocity of collectively migrating cells. The model predicts that cohesotaxis and tissue geometry in combination promote cooperative migration of leader cells resulting in increased migration velocity of the collective. Radial intercalation of cells towards the substrate is an additional mechanism to increase migratory speed of the tissue. Summary Statement: We present a novel Cellular-Potts model of collective cell migration to investigate the relative roles of cohesotaxis, tissue geometry, and cell intercalation on migration velocity of Xenopus mesendoderm.

Renin Cell Baroreceptor, a Nuclear Mechanotransducer Central for Homeostasis.

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Extracellular Matrix (ECM) and the Sculpting of Embryonic Tissues.

Extracellular matrices (ECMs) are structurally and compositionally diverse networks of collagenous and noncollagenous glycoproteins, glycosaminoglycans, proteoglycans, and associated molecules that together comprise the metazoan matrisome. Proper deposition and assembly of ECM is of profound importance to cell proliferation, survival, and differentiation, and the morphogenesis of tissues and organ systems that define sequential steps in the development of all animals. Importantly, it is now clear that the instructive influence of a particular ECM at various points in development reflects more than a simple summing of component parts; cellular responses also reflect the dynamic assembly and changing topology of embryonic ECM, which in turn affect its biomechanical properties. This review highlights recent advances in understanding how biophysical features attributed to ECM, such as stiffness and viscoelasticity, play important roles in the sculpting of embryonic tissues and the regulation of cell fates. Forces generated within cells and tissues are transmitted both through integrin-based adhesions to ECM, and through cadherin-dependent cell-cell adhesions; the resulting short- and long-range deformations of embryonic tissues drive morphogenesis. This coordinate regulation of cell-ECM and cell-cell adhesive machinery has emerged as a common theme in a variety of developmental processes. In this review we consider select examples in the embryo where ECM is implicated in setting up tissue barriers and boundaries, in resisting pushing or pulling forces, or in constraining or promoting cell and tissue movement. We reflect on how each of these processes contribute to morphogenesis.

FAK is required for tension-dependent organization of collective cell movements in Xenopus mesendoderm.

Collective cell movements are integral to biological processes such as embryonic development and wound healing and also have a prominent role in some metastatic cancers. In migrating Xenopus mesendoderm, traction forces are generated by cells through integrin-based adhesions and tension transmitted across cadherin adhesions. This is accompanied by assembly of a mechanoresponsive cadherin adhesion complex containing keratin intermediate filaments and the catenin-family member plakoglobin. We demonstrate that focal adhesion kinase (FAK), a major component of integrin adhesion complexes, is required for normal morphogenesis at gastrulation, closure of the anterior neural tube, axial elongation and somitogenesis. Depletion of zygotically expressed FAK results in disruption of mesendoderm tissue polarity similar to that observed when expression of keratin or plakoglobin is inhibited. Both individual and collective migrations of mesendoderm cells from FAK depleted embryos are slowed, cell protrusions are disordered, and cell spreading and traction forces are decreased. Additionally, keratin filaments fail to organize at the rear of cells in the tissue and association of plakoglobin with cadherin is diminished. These findings suggest that FAK is required for the tension-dependent assembly of the cadherin adhesion complex that guides collective mesendoderm migration, perhaps by modulating the dynamic balance of substrate traction forces and cell cohesion needed to establish cell polarity.

Cadherin adhesion, tissue tension, and noncanonical Wnt signaling regulate fibronectin matrix organization.

In this study we demonstrate that planar cell polarity signaling regulates morphogenesis in Xenopus embryos in part through the assembly of the fibronectin (FN) matrix. We outline a regulatory pathway that includes cadherin adhesion and signaling through Rac and Pak, culminating in actin reorganization, myosin contractility, and tissue tension, which, in turn, directs the correct spatiotemporal localization of FN into a fibrillar matrix. Increased mechanical tension promotes FN fibril assembly in the blastocoel roof (BCR), while reduced BCR tension inhibits matrix assembly. These data support a model for matrix assembly in tissues where cell-cell adhesions play an analogous role to the focal adhesions of cultured cells by transferring to integrins the tension required to direct FN fibril formation at cell surfaces.

Fibrillins can co-assemble in fibrils, but fibrillin fibril composition displays cell-specific differences.

Fibrillins are microfibril-forming extracellular matrix macromolecules that modulate skeletal development. In humans, mutations in fibrillins result in long bone overgrowth as well as other distinct phenotypes. Whether fibrillins form independent microfibrillar networks or can co-polymerize, forming a single microfibril, is not known. However, this knowledge is required to determine whether phenotypes arise because of loss of singular or composite functions of fibrillins. Immunolocalization experiments using tissues and de novo matrices elaborated by cultured cells demonstrated that both fibrillins can be present in the same individual microfibril in certain tissues and that both fibrillins can co-polymerize in fibroblast cultures. These studies suggest that the molecular information directing fibrillin fibril formation may be similar in both fibrillins. Furthermore, these studies provide a molecular basis for compensation of one fibrillin by the other during fetal life. In postnatal tissues, fibrillin-2 antibodies demonstrated exuberant staining in only one location: peripheral nerves. This surprising finding implicates distinct functions for fibrillin-2 in peripheral nerves, because a unique feature in humans and in mice mutant for fibrillin-2 is joint contractures that resolve over time.