A central challenge in biology is to understand the cellular processes that direct morphogenesis and the formation of the basic body plan during development. These events are controlled to large extend, by adhesive interactions of cells with one another and with their extracellular environments. The research proposed for the next project period will investigate molecular mechanisms of cell-extracellular matrix (ECM) adhesion mediated by integrin receptors. The primary goal is to establish the functional contribution of integrins to the morphogenetic processes that help shape the early amphibian embryo. In order to better understand integrin function and expression in embryogenesis, full-length cDNA clones encoding multiple integrin alpha subunits will be obtained from Xenopus lambdacDNA libraries. These cDNAs will be used to prepare bacterial fusion proteins for the purposes of generating and characterizing monoclonal and polyclonal antibodies. Xenopus tissue culture cells will also be used as immunogen to produce monoclonal antibodies that block integrin function. Immunocytochemistry and in situ hybridization methods will be utilized in order to determine the spatial and temporal patterns of integrin mRNA and protein expression in embryos. Several approaches will then be employed to analyze the functions of specific integrin receptors. Integrin transcripts will be injected into eggs and specific blastomeres and the adhesion, migration and fate of the progeny determined as development proceeds. The adhesive and migratory behaviors of normal embryonic cells and those over- expressing specific integrins will be compared in vitro on a variety of ECM substrates. Function-blocking antibodies will also be used to perturb integrin function in in vitro adhesion assays and in vivo by microinjection. Changes in integrin mediated cell adhesion in response to induction will be studied using cells and explants derived from embryos injected with transcripts encoding peptides known to induce mesoderm. The control of integrin expression and/or the activation of integrin ligand binding activity in activin-induced tissues will also be investigated at the mRNA and protein levels.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Cellular Biology and Physiology Subcommittee 1 (CBY)
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University of Virginia
Schools of Medicine
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Rozario, Tania; Mead, Paul E; DeSimone, Douglas W (2014) Diverse functions of kindlin/fermitin proteins during embryonic development in Xenopus laevis. Mech Dev 133:203-17
Bjerke, Maureen A; Dzamba, Bette J; Wang, Chong et al. (2014) FAK is required for tension-dependent organization of collective cell movements in Xenopus mesendoderm. Dev Biol 394:340-56
DeSimone, Douglas W; Horwitz, A Rick (2014) Cell Biology. Many modes of motility. Science 345:1002-3
Weber, Gregory F; Bjerke, Maureen A; DeSimone, Douglas W (2012) A mechanoresponsive cadherin-keratin complex directs polarized protrusive behavior and collective cell migration. Dev Cell 22:104-15
Wei, Shuo; Xu, Guofeng; Bridges, Lance C et al. (2012) Roles of ADAM13-regulated Wnt activity in early Xenopus eye development. Dev Biol 363:147-54
Schwarzbauer, Jean E; DeSimone, Douglas W (2011) Fibronectins, their fibrillogenesis, and in vivo functions. Cold Spring Harb Perspect Biol 3:
Weber, Gregory F; Bjerke, Maureen A; DeSimone, Douglas W (2011) Integrins and cadherins join forces to form adhesive networks. J Cell Sci 124:1183-93
Wei, Shuo; Xu, Guofeng; Bridges, Lance C et al. (2010) ADAM13 induces cranial neural crest by cleaving class B Ephrins and regulating Wnt signaling. Dev Cell 19:345-52
Wei, Shuo; Whittaker, Charles A; Xu, Guofeng et al. (2010) Conservation and divergence of ADAM family proteins in the Xenopus genome. BMC Evol Biol 10:211
Rozario, Tania; DeSimone, Douglas W (2010) The extracellular matrix in development and morphogenesis: a dynamic view. Dev Biol 341:126-40

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