title: Cross-Scale Integrin Regulation Organizes ECM and Tissue Topology.
abstract: The diverse morphologies of animal tissues are underlain by different configurations of adherent cells and extracellular matrix (ECM). Here, we elucidate a cross-scale mechanism for tissue assembly and ECM remodeling involving Cadherin 2, the ECM protein Fibronectin, and its receptor Integrin α5. Fluorescence cross-correlation spectroscopy within the zebrafish paraxial mesoderm mesenchyme reveals a physical association between Integrin α5 on adjacent cell membranes. This Integrin-Integrin complex correlates with conformationally inactive Integrin. Cadherin 2 stabilizes both the Integrin association and inactive Integrin conformation. Thus, Integrin repression within the adherent mesenchymal interior of the tissue biases Fibronectin fibrillogenesis to the tissue surface lacking cell-cell adhesions. Along nascent somite boundaries, Cadherin 2 levels decrease, becoming anti-correlated with levels of Integrin α5. Simultaneously, Integrin α5 clusters and adopts the active conformation and then commences ECM assembly. This cross-scale regulation of Integrin activation organizes a stereotypic pattern of ECM necessary for vertebrate body elongation and segmentation.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
authors.forename: Dörthe
authors.initials: D
authors.lastname: Jülich
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA.
authors.forename: Garrett
authors.initials: G
authors.lastname: Cobb
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Melo
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: McMillen
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Lawton
authors.affiliation: Department of Physics, Yale University, New Haven, CT 06511, USA.
authors.forename: Simon G J
authors.initials: SG
authors.lastname: Mochrie
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rhoades
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06511, USA. Electronic address: scott.holley@yale.edu.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Holley
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D019170:Somites / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D015820:Cadherins; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D016023:Integrins; D029961:Zebrafish Proteins