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- Novel dynamics and functions of Fibronectin in early vertebrate developmentPublication . Gomes De Almeida, Patrícia; Thorsteinsdóttir, Sólveig; Palmeirim, Isabel; Andrade, Raquel P.The metameric body plan of vertebrates is established during somitogenesis, one of the most complex morphogenetic events during development. Somites epithelialize periodically from the anterior-most presomitic mesoderm, and this rhythmicity is thought to be controlled by cyclic traveling waves of gene expression that sweep the tissue anteriorly. Although the spatial and temporal regulation of somitogenesis has been extensively studied, how the periodicity of genetic oscillations is translated into periodic somite epithelialization remains elusive. Furthermore, while knockout experiments have implicated the extracellular matrix component fibronectin in somite formation, much of the roles of its qualitative features deriving from its assembly state are still unknown. The aim of this thesis is to re-address the role of fibronectin during paraxial mesoderm development, particularly during somite morphogenesis. In Chapter 2, we describe fibronectin production and assembly dynamics during early embryogenesis and found that it is highly dynamic throughout paraxial mesoderm development, as different forms of fibronectin assembly (autocrine vs paracrine) correlate with exquisite morphogenetic events. In Chapter 3 we re-address the role of fibronectin during somite formation in vivo. We show that an intact fibronectin matrix and downstream mechanotransduction signaling are required for correct segmentation clock dynamics and somite morphogenesis. Our results suggest that the fibronectin matrix and its downstream chemical and mechanical cues couple genetic oscillations with timely somite morphogenesis. In Chapter 4 we investigate the role of fibronectin in somite maturation. We demonstrate that normal fibronectin assembly is required for correct Sonic hedgehog signaling in the somite, which in turn controls fibronectin production in this tissue, suggesting that fibronectin and Sonic cooperate to orchestrate somite patterning and differentiation. This thesis demonstrates that fibronectin is a dynamic pivotal player regulating paraxial mesoderm development. It also highlights the previously unappreciated importance of the extracellular matrix and its derived mechanical cues during embryonic development.
- Cell–Fibronectin Interactions and Actomyosin Contractility Regulate the Segmentation Clock and Spatio-Temporal Somite Cleft Formation during Chick Embryo SomitogenesisPublication . Gomes De Almeida, Patrícia; Rifes, Pedro; Martins-Jesus, Ana P.; Pinheiro, Gonçalo G.; Andrade, Raquel P.; Thorsteinsdottir, SolveigFibronectin is essential for somite formation in the vertebrate embryo. Fibronectin matrix assembly starts as cells emerge from the primitive streak and ingress in the unsegmented presomitic mesoderm (PSM). PSM cells undergo cyclic waves of segmentation clock gene expression, followed by Notch-dependent upregulation of meso1 in the rostral PSM which induces somite cleft formation. However, the relevance of the fibronectin matrix for these molecular processes remains unknown. Here, we assessed the role of the PSM fibronectin matrix in the spatio-temporal regulation of chick embryo somitogenesis by perturbing (1) extracellular fibronectin matrix assembly, (2) integrin–fibronectin binding, (3) Rho-associated protein kinase (ROCK) activity and (4) non-muscle myosin II (NM II) function. We found that integrin–fibronectin engagement and NM II activity are required for cell polarization in the nascent somite. All treatments resulted in defective somitic clefts and significantly perturbed meso1 and segmentation clock gene expression in the PSM. Importantly, inhibition of actomyosin-mediated contractility increased the period of hairy1/hes4 oscillations from 90 to 120 min. Together, our work strongly suggests that the fibronectin–integrin–ROCK–NM II axis regulates segmentation clock dynamics and dictates the spatio-temporal localization of somitic clefts.