Biology subjects

DeSimone, D. W.

Publications and source records attributed to DeSimone, D. W..

3 recordsLinked to original sources

bioRxiv2023

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 StatementWe 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

developmental biology↗

bioRxiv2018

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.

developmental biology↗

bioRxiv2018

Integrin and ligand-independent PDGFr signaling synergistically contribute to directional migration of Xenopus mesendoderm

Both PDGF signaling and adhesion to fibronectin (FN) matrix have been implicated in the directional collective migration of Xenopus mesendoderm cells at gastrulation. However, mesendoderm explants cultured on FN-coated substrates migrate directionally even in the absence of a source of PDGF. Integrin adhesion has been reported to up-regulate PDGF ligand-independent signaling through the PDGF receptor (PDGFr) in cultured mammalian cells. In order to address whether a similar mechanism stimulates PDGFr signaling in the absence of PDGF-A ligand in amphibian mesendoderm, isolated cells were cultured on bacterial fusion proteins containing the Type-III repeats 9-11 of FN (GST-9.11). Type III9-11 contains the RGD and \"synergy\" (PPSRN) sites required for integrin 5{beta}1 adhesion and activation but lacks the PDGF-A ligand-binding site present in the full-length FN protein. In order to ensure mesendoderm was not exposed to PDGF in vivo prior to removal and culture in vitro, antisense morpholinos were used to inhibit normal expression of PDGF-A ligand in embryos. P-Akt levels were reduced two-fold when either the PDGFr- was knocked down or when cells were plated on GST-9.11a, which contains a point mutation (PPSRN>PPSAN) that prevents both full activation of integrin 5{beta}1 and cell spreading. Reduced expression of PDGFr- was accompanied by perturbations in tissue migration, cytoskeletal organization, polarity of cell protrusions, and focal adhesion area. Mesendoderm cells became rounded, and the actin and cytokeratin filaments appeared collapsed and often colocalized near the cell center. Taken together, these findings suggest that integrin adhesion to FN, acting in synergy with PDGFr-, is sufficient to elevate PI3K-Akt signaling in the mesendoderm even in the absence of the PDGF-A ligand, and to promote forward-directed protrusions and directional tissue migration.

developmental biology↗