Essential role for fibrillin-2 in zebrafish notochord and vascular morphogenesis. Dev Dyn

Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Developmental Dynamics (Impact Factor: 2.38). 10/2008; 237(10):2844-61. DOI: 10.1002/dvdy.21705
Source: PubMed


Recent studies demonstrate that lysyl oxidase cuproenzymes are critical for zebrafish notochord formation, but the molecular mechanisms of copper-dependent notochord morphogenesis are incompletely understood. We, therefore, conducted a forward genetic screen for zebrafish mutants that exhibit notochord sensitivity to lysyl oxidase inhibition, yielding a mutant with defects in notochord and vascular morphogenesis, puff daddygw1 (pfdgw1). Meiotic mapping and cloning reveal that the pfdgw1 phenotype results from disruption of the gene encoding the extracellular matrix protein fibrillin-2, and the spatiotemporal expression of fibrillin-2 is consistent with the pfdgw1 phenotype. Furthermore, each aspect of the pfdgw1 phenotype is recapitulated by morpholino knockdown of fibrillin-2. Taken together, the data reveal a genetic interaction between fibrillin-2 and the lysyl oxidases in notochord formation and demonstrate the importance of fibrillin-2 in specific early developmental processes in zebrafish.

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    • "Knockdown of fibronectin or fibrillin by antisense morpholinos in Xenopus causes defects in convergent extension of the notochord and presomitic mesoderm (Davidson et al., 2006; Skoglund et al., 2006) although in the case of fibronectin the importance of fibrils is less clear (Rozario et al., 2009; discussed further below). Structural support for notochord elongation may rely on other ECM proteins such as fibrillin (Gansner et al., 2008; Skoglund et al., 2006; Bette Dzamba, personal communication). "
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    ABSTRACT: The extracellular matrix (ECM) is synthesized and secreted by embryonic cells beginning at the earliest stages of development. Our understanding of ECM composition, structure and function has grown considerably in the last several decades and this knowledge has revealed that the extracellular microenvironment is critically important for cell growth, survival, differentiation and morphogenesis. ECM and the cellular receptors that interact with it mediate both physical linkages with the cytoskeleton and the bidirectional flow of information between the extracellular and intracellular compartments. This review considers the range of cell and tissue functions attributed to ECM molecules and summarizes recent findings specific to key developmental processes. The importance of ECM as a dynamic repository for growth factors is highlighted along with more recent studies implicating the 3-dimensional organization and physical properties of the ECM as it relates to cell signaling and the regulation of morphogenetic cell behaviors. Embryonic cell and tissue generated forces and mechanical signals arising from ECM adhesion represent emerging areas of interest in this field.
    Full-text · Article · Oct 2009 · Developmental Biology
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    • "Subsequent analyses of fibrillin mutant mice have corroborated and extended the concept that elastic macro-aggregates define physically discrete tissue compartments and/or guide functionally distinct developmental programs (Ramirez et al. 2007). More recent genetic perturbations in frog and zebrafish embryos have demonstrated the phylogenetic importance of microfibrils in vertebrate development, in addition to reiterating the organ-specific roles of fibrillin proteins (Skoglund and Keller 2007; Gansner et al. 2008). "
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    ABSTRACT: Fibrillin-1 and fibrillin-2 are large cysteine-rich glycoproteins that serve two key physiological functions: as supporting structures that impart tissue integrity and as regulators of signaling events that instruct cell performance. The structural role of fibrillins is exerted through the temporal and hierarchical assembly of microfibrils and elastic fibers, whereas the instructive role reflects the ability of fibrillins to sequester transforming growth factor beta (TGFbeta) and bone morphogenetic protein (BMP) complexes in the extracellular matrix. Characterization of fibrillin mutations in human patients and in genetically engineered mice has demonstrated that perturbation of either function manifests in disease. More generally, these studies have indicated that fibrillins are integral components of a broader biological network of extracellular, cell surface, and signaling molecules that orchestrate morphogenetic and homeostatic programs in multiple organ systems. They have also suggested that the relative composition of fibrillin-rich microfibrils imparts contextual specificity to TGFbeta and BMP signaling by concentrating the ligands locally so as to regulate cell differentiation within a spatial context during organ formation (positive regulation) and by restricting their bioavailability so as to modulate cell performance in a timely fashion during tissue remodeling/repair (negative regulation). Correlative evidence suggests functional coupling of the cell-directed assembly of microfibrils and targeting of TGFbeta and BMP complexes to fibrillins. Hence, the emerging view is that fibrillin-rich microfibrils are molecular integrators of structural and instructive signals, with TGFbeta and BMPs as the nodal points that convert extracellular inputs into discrete and context-dependent cellular responses.
    Full-text · Article · Jul 2009 · Cell and Tissue Research
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