Fibronectin is a smart adhesive that both influences and responds to the mechanics of early spinal column development

An extracellular matrix of Fibronectin adheres the neural tube to the two flanking columns of paraxial mesoderm and is required for normal vertebrate development. Here, we find that the bilaterally symmetric interfaces between the zebrafish neural tube and paraxial mesoderm function as optimally engineered adhesive lap joints with rounded edges, graded Fibronectin ‘adhesive’ and an arced adhesive spew filet. Fibronectin is a ‘smart adhesive’ that remodels to the lateral edges of the neural tube-paraxial mesoderm interfaces where shear stress is highest. Fibronectin remodeling is mechanically responsive to contralateral variation morphogenesis, and Fibronectin-mediated inter-tissue adhesion is required for bilaterally symmetric morphogenesis of the paraxial mesoderm. Strikingly, however, perturbation of the Fibronectin matrix rescues the neural tube convergence defect of cadherin 2 mutants. Therefore, Fibronectin-mediated inter-tissue adhesion dynamically coordinates bilaterally symmetric morphogenesis of the vertebrate trunk but predisposes the neural tube to convergence defects that lead to spina bifida.

Fibronectin-dependent tissue mechanics regulate the translation of segmentation clock oscillations into periodic somite formation

Somitogenesis starts with cyclic waves of expression of segmentation clock genes in the presomitic mesoderm (PSM) and culminates with periodic budding of somites in its anterior-most region. How cyclic clock gene expression is translated into timely morphological somite formation has remained unclear. A posterior to anterior gradient of increasing PSM tissue cohesion correlates with increasing fibronectin matrix complexity around the PSM, suggesting that fibronectin-dependent tissue mechanics may be involved in this transition. Here we address whether the mechanical properties of the PSM tissue play a role in regulating the pathway leading to cleft formation in the anterior PSM. We first interfered with cytoskeletal contractility in the chick PSM by disrupting actomyosin-mediated contractility directly or via Rho-associated protein kinase function. Then we perturbed fibronectin matrix accumulation around the PSM tissue by blocking integrin-fibronectin binding or fibronectin matrix assembly. All four treatments perturbed hairy1 and meso1 expression dynamics and resulted in defective somitic clefts. A model is presented where a gradient of fibronectin-dependent tissue mechanics participates in the PSM wavefront of maturation by ensuring the correct spatio-temporal conversion of cyclic segmentation clock gene expression into periodic somite formation.

Tumor cell-organized fibronectin is required to maintain a dormant breast cancer population

Tumors can undergo long periods of dormancy, with cancer cells entering a largely quiescent, non-proliferative state before reactivation and outgrowth. For a patient, these post-remission tumors are often drug resistant and highly aggressive, resulting in poor prognosis. To understand the role of the extracellular matrix (ECM) in regulating tumor dormancy, we created anin vitrocell culture system that combines carefully controlled ECM substrates with nutrient deprivation to observe entranceintoand exitfromdormancy with live imaging. We saw that cell populations capable of surviving entrance into long-term dormancy were heterogeneous, containing quiescent, cell cycle arrested, and actively proliferating cells. Cell populations that endured extended periods of serum-deprivation-induced dormancy formed an organized, fibrillar fibronectin matrix via αvβ3and α5β1integrin adhesion, ROCK-generated tension, and TGFβ2 stimulation. We surmised that the fibronectin matrix was primarily a mediator of cell survival, not proliferation, during the serum-deprivation stress, bacause cancer cell outgrowth after dormancy required MMP-2-mediated fibronectin degradation. Given the difficulty of animal models in observing entrance and exit from dormancy in real-time, we propose this approach as a new,in vitromethod to study factors important in regulating dormancy, and we used it here to elucidate a role for fibronectin deposition and MMP activation.

Multiple functions for the catenin family member plakoglobin in cadherin-dependent adhesion, fibronectin matrix assembly and Xenopus gastrulation movements

Shaping an embryo requires tissue-scale cell rearrangements known as morphogenetic events. These force-dependent processes require cells to adhere to their neighbors, through cadherin-catenin complexes, and to their extracellular matrix substrates, through integrin-based focal contacts. Integrin receptors are not only important for attachment to the extracellular matrix, but also for its fibrillar assembly. Fibrillogenesis requires actomyosin contractility, regulated in part by cadherin-catenin complexes. One such catenin, plakoglobin, mediates the attachment of actin stress fibers to cadherin cytoplasmic tails through its interactions with actin-binding proteins. In Xenopus gastrulae, plakoglobin has been identified as an essential member in the force-induced collective migration of the mesendoderm tissue. In the current study, we have further characterized the role of plakoglobin in two additional morphogenetic processes, epiboly and convergent extension. Plakoglobin-deficient tadpoles are 40% shorter and gastrulae contain notochords that are 60% wider than stage-matched controls, indicating convergent extension defects. The radially intercalating ectoderm of morphant animal caps is nearly twice as thick as controls. Furthermore, morphant embryos exhibit a failure to assemble a fibronectin matrix at the notochord-somite-boundary or along the blastocoel roof. The loss of the fibronectin matrix, while not due to changes in overall patterning, is a result of a failure to assemble the soluble dimers into long fibrils. The force of attachment to a cadherin or fibronectin substrate is reduced in plakoglobin morphants, indicating defects in adhesion to both cadherin and fibronectin. These data suggest that plakoglobin regulates morphogenesis and fibronectin assembly through cell-cell and cell-matrix adhesion.