Thrombospondin-mediated adhesion is essential for the formation of the myotendinous junction in<i>Drosophila</i>

Subramanian, Arul; Wayburn, Bess; Bunch, Thomas A.; Volk, Talila

doi:10.1242/dev.000406

Cited by 95 publications

(123 citation statements)

References 33 publications

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“…Mice that lack Thbs2 display connective tissue abnormalities, including in tendons (Kyriakides et al, 1998). The Drosophila equivalent, Thrombospondin (Tsp), is produced by tendon cells and is essential for the formation of the integrinmediated myotendinous junction (Subramanian et al, 2007). We believe that these genes that are differentially expressed in limb tendon cells during mouse development (listed in Table 3; supplementary material Table S1) constitute an important list of tendon markers.…”

Section: Genes Expressed In Limb Tendons Cells During Mouse Developmentmentioning

confidence: 99%

Transcriptomic analysis of mouse limb tendon cells during development

et al. 2014

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The molecular signals driving tendon development are not fully identified. We have undertaken a transcriptome analysis of mouse limb tendon cells that were isolated at different stages of development based on scleraxis (Scx) expression. Microarray comparisons allowed us to establish a list of genes regulated in tendon cells during mouse limb development. Bioinformatics analysis of the tendon transcriptome showed that the two most strongly modified signalling pathways were TGF-β and MAPK. TGF-β/SMAD2/3 gain-and loss-offunction experiments in mouse limb explants and mesenchymal stem cells showed that TGF-β signalling was sufficient and required via SMAD2/3 to drive mouse mesodermal stem cells towards the tendon lineage ex vivo and in vitro. TGF-β was also sufficient for tendon gene expression in late limb explants during tendon differentiation. FGF does not have a tenogenic effect and the inhibition of the ERK MAPK signalling pathway was sufficient to activate Scx in mouse limb mesodermal progenitors and mesenchymal stem cells.

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Section: Genes Expressed In Limb Tendons Cells During Mouse Developmentmentioning

confidence: 99%

Transcriptomic analysis of mouse limb tendon cells during development

et al. 2014

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“…ECM ligands are a diverse group of molecules that are secreted by cells, creating local environments and matrices that modulate cell interactions. Mutations in integrins or their ECM ligands have been shown to disrupt cell adhesion, resulting in wing blistering (1, 3-5, 7, 9 -12), muscle detachment (3,13,14), and defects in dorsal closure (15) in Drosophila, as well as the human disease epidermolysis bullosa, in which the epidermal and dermal skin layers are separated (16,17). Loss of proper cell adhesive properties is also a hallmark of cancer progression and metastasis.…”

mentioning

confidence: 99%

An O-Glycosyltransferase Promotes Cell Adhesion during Development by Influencing Secretion of an Extracellular Matrix Integrin Ligand

Zhang

Tran

Hagen

2010

Journal of Biological Chemistry

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Protein secretion and localization are crucial during eukaryotic development, establishing local cell environments as well as mediating cell interactions, signaling, and adhesion. In this study, we demonstrate that the glycosyltransferase, pgant3, specifically modulates integrin-mediated cell adhesion by influencing the secretion and localization of the integrin ligand, Tiggrin. We demonstrate that Tiggrin is normally O-glycosylated and localized to the basal matrix where the dorsal and ventral cell layers adhere in wild type Drosophila wings. In pgant3 mutants, Tiggrin is no longer O-glycosylated and fails to be properly secreted to this basal cell layer interface, resulting in disruption of integrin-mediated cell adhesion in the wing. pgant3-mediated effects are dependent on enzymatic activity, as mutations that form a stable protein yet abrogate O-glycosyltransferase activity result in Tiggrin accumulation within the dorsal and ventral cells comprising the wing. Our results provide the first in vivo evidence for the role of O-glycosylation in the secretion of specific extracellular matrix proteins, thus altering the composition of the cellular "microenvironment" and thereby modulating developmentally regulated cell adhesion events. As alterations in cell adhesion are a hallmark of cancer progression, this work provides insight into the long-standing association between aberrant O-glycosylation and tumorigenesis.

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“…Thus ECM retention appears likely to be an ancestral activity of TSPs. This is borne out by the recently reported functional role of the single TSP of Drosophila, D-TSP, in the ECM of muscle-tendon attachment sites and the localisation of a prawn TSP to specialised ECM structures -oocyte cortical rods (Yamano et al, 2004; Chanana et al, 2007;Subramanian et al, 2007).Studies of cell-attachment activities of TSP1 and TSP2 have relied on purified TSPs coated onto glass or plastic surfaces, where they probably form a uniform layer of individual trimers. Using classic procedures for isolation of insoluble ECM, we demonstrate that TSP1 and other TSPs are retained in ECM in the physical form of small, closely spaced puncta.…”

mentioning

confidence: 99%

Extracellular matrix retention of thrombospondin 1 is controlled by its conserved C-terminal region

Adams

Bentley

Kvansakul

et al. 2008

Journal of Cell Science

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domain or type 1 repeats. Using a novel mRFP-tagged TSP1 C-terminal trimer, we demonstrate that ECM retention involves the RGD site and a novel site in the L-lectin domain with structural similarity to the ligand-binding site of cargo transport proteins. CD47 and ␤1 integrins are dispensable for ECM retention, but ␤1 integrins enhance activity. These novel data advance concepts of the molecular processes that lead to ECM retention of TSP1. Journal of Cell Science Matrix retention of thrombospondinsTSP2 is present in cartilage and various connective tissues (Bornstein et al., 2004). TSP4 is present in the ECM of the nervous system, at neuromuscular junctions, in the developing retina, adult eye and tendon (Arber and Caroni, 1995; Hauser et al., 1995;Stenina et al., 2003; Dunkle et al., 2007). TSP5 or COMP (cartilage oligomeric matrix protein) is a component of ECM in cartilage, synovium and tendon, which associates with collagen fibrils and binds collagens II and IX, matrilin-3 and fibronectin in vitro (Hedbom et al., 1992; DiCesare et al., 1995; DiCesare et al., 1997; DiCesare et al., 2002;Sodersten et al., 2005). In vivo models and human diseases provide evidence that TSPs contribute functionally to ECM organisation and can modulate the adhesive or structural properties of ECM. For example, TSP2-null mice have aberrant assembly of collagen fibrils because of reduced cell surface tissue transglutaminase, resulting in lax tendons and decreased tensile strength of the skin (Kyriakides et al., 1998; Agah et al., 2005). Interaction of Drosophila TSP (D-TSP) with ␣PS2 integrin on muscle cells is needed for stable tendon and muscle attachment during development (Chanana et al., 2007;Subramanian et al., 2007). Polymorphisms in the coding sequences of human THBS1 and THBS4, which predispose to cardiovascular disease, enhance platelet aggregation in the case of TSP1 and affect endothelial cell adhesion in the case of TSP4 (Stenina et al., 2007).In vitro binding assays with purified proteins have demonstrated that TSPs can bind to multiple structural ECM components and to various growth factors that may themselves bind ECM (reviewed by Adams, 2001). These findings indicate targets for binding by extracellular TSPs, but do not address the molecular processes by which TSPs come to be retained within ECM. Knowledge of these processes is important with regard to the clear biological significance of TSPs in connective ECM, tumour biology, immune response, synaptogenesis and vascular function. Prospective therapeutic modulations or construction of synthetic ECM would also benefit from this knowledge. Until recently, the ability to analyse these mechanisms was hampered by a lack of understanding of the complex structure of TSP polypeptides, particularly the large and highly conserved C-terminal region. In recent years, structures for all the major domains of TSP1 and TSP2 have been solved at the atomic level (Tan et al., 2002;Tan et al., 2006;Kvansakul et al., 2004; Carlson et al., 2005). We demonstrate here that ECM retention...

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Thrombospondin-mediated adhesion is essential for the formation of the myotendinous junction inDrosophila

Cited by 95 publications

References 33 publications

Transcriptomic analysis of mouse limb tendon cells during development

Transcriptomic analysis of mouse limb tendon cells during development

An O-Glycosyltransferase Promotes Cell Adhesion during Development by Influencing Secretion of an Extracellular Matrix Integrin Ligand

Extracellular matrix retention of thrombospondin 1 is controlled by its conserved C-terminal region

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