Thrombospondin-1 Promotes Circuit-Specific Synapse Formation Via β1-Integrin

Thrombospondin-1 Promotes Circuit-Specific Synapse Formation via β1-Integrin

10.1101/866590 ◽

2019 ◽

Author(s):

Sehwon Koh ◽

Suva Roy ◽

Oznur Eroglu ◽

Samuel Strader ◽

William J. Chen ◽

...

Keyword(s):

Glial Cells ◽

Synapse Formation ◽

Excitatory Synapse ◽

Synaptic Connectivity ◽

Β1 Integrin ◽

Laminar Organization ◽

Synaptic Circuits ◽

Conditional Deletion ◽

Subtype Specificity ◽

Thrombospondin 1

SUMMARYGlial cells regulate synaptic connectivity during development, but whether they selectively instruct the formation of specific synaptic circuits is not known. Here we show that the major perisynaptic glia of the retina, the Muller glia (MG), control the proper establishment of the direction-selective (DS) circuit by a synaptogenic protein, Thrombospondin 1 (TSP1). We found that TSP1 promotes excitatory synapse formation specifically in on-off Direction-Selective retinal Ganglion Cells (ooDSGCs). Lack of TSP1 leads to reduced synapse formation within the inner plexiform sublayers containing DS-circuit, resulting in deficits of ooDSGC function. Even though pan-TSP receptor, α2δ-1, interaction is required for TSP1-induced synapse formation, the ooDSGC-subtype specificity of TSP1 is conferred by a second neuronal TSP1 receptor, β1-Integrin. Furthermore, conditional deletion of β1-Integrin in ooDSGCs results in diminished excitatory synapse formation without disturbing laminar organization showing that MG-secreted TSP1 controls circuit-specific synapse formation via β1-Integrin.

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Thrombospondin-1 in maladaptive aging responses: a concept whose time has come

AJP Cell Physiology ◽

10.1152/ajpcell.00089.2020 ◽

2020 ◽

Vol 319 (1) ◽

pp. C45-C63

Author(s):

Jeffrey S. Isenberg ◽

David D. Roberts

Keyword(s):

Molecular Mechanisms ◽

Synapse Formation ◽

Genotoxic Stress ◽

Cell Types ◽

Cellular Tissue ◽

Therapeutic Agents ◽

Age Related ◽

Organ Systems ◽

Age Dependent ◽

Thrombospondin 1

Numerous age-dependent alterations at the molecular, cellular, tissue and organ systems levels underlie the pathophysiology of aging. Herein, the focus is upon the secreted protein thrombospondin-1 (TSP1) as a promoter of aging and age-related diseases. TSP1 has several physiological functions in youth, including promoting neural synapse formation, mediating responses to ischemic and genotoxic stress, minimizing hemorrhage, limiting angiogenesis, and supporting wound healing. These acute functions of TSP1 generally require only transient expression of the protein. However, accumulating basic and clinical data reinforce the view that chronic diseases of aging are associated with accumulation of TSP1 in the extracellular matrix, which is a significant maladaptive contributor to the aging process. Identification of the relevant cell types that chronically produce and respond to TSP1 and the molecular mechanisms that mediate the resulting maladaptive responses could direct the development of therapeutic agents to delay or revert age-associated maladies.

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The Thrombospondin Receptor CD47 (IAP) Modulates and Associates with α2β1 Integrin in Vascular Smooth Muscle Cells

Molecular Biology of the Cell ◽

10.1091/mbc.9.4.865 ◽

1998 ◽

Vol 9 (4) ◽

pp. 865-874 ◽

Cited By ~ 118

Author(s):

Xue-Qing Wang ◽

William A. Frazier

Keyword(s):

Smooth Muscle ◽

Monoclonal Antibodies ◽

Smooth Muscle Cells ◽

Type I Collagen ◽

Muscle Cells ◽

Type I ◽

Β1 Integrin ◽

Thrombospondin 1 ◽

Carboxyl Terminal ◽

Α2β1 Integrin

The carboxyl-terminal domain of thrombospondin-1 enhances the migration and proliferation of smooth muscle cells. Integrin-associated protein (IAP or CD47) is a receptor for the thrombospondin-1 carboxyl-terminal cell-binding domain and binds the agonist peptide 4N1K (kRFYVVMWKk) from this domain. 4N1K peptide stimulates chemotaxis of both human and rat aortic smooth muscle cells on gelatin-coated filters. The migration on gelatin is specifically blocked by monoclonal antibodies against IAP and a β1 integrin, rather than αvβ3 as found previously for 4N1K-stimulated chemotaxis of endothelial cells on gelatin. Both human and rat smooth muscle cells displayed a weak migratory response to soluble type I collagen; however, the presence of 4N1K peptide or intact thrombospondin-1 provoked a synergistic chemotactic response that was partially blocked by antibodies to α2 and β1 integrin subunits and to IAP. A combination of antiα2 and IAP monoclonal antibodies completely blocked chemotaxis. RGD peptide and antiαvβ3 mAb were without effect. 4N1K and thrombospondin-1 did not augment the chemotactic response of smooth muscle cells to fibronectin, vitronectin, or collagenase-digested type I collagen. Complex formation between α2β1 and IAP was detected by the coimmunoprecipitation of both α2 and β1 integrin subunits with IAP. These data suggest that IAP can associate with α2β1 integrin and modulate its function.

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β1 Integrin Cytoplasmic Variants Differentially Regulate Expression of the Antiangiogenic Extracellular Matrix Protein Thrombospondin 1

Cancer Research ◽

10.1158/0008-5472.can-09-0186 ◽

2009 ◽

Vol 69 (13) ◽

pp. 5374-5382 ◽

Cited By ~ 10

Author(s):

Hira Lal Goel ◽

Loredana Moro ◽

Joanne E. Murphy-Ullrich ◽

Chung-Cheng Hsieh ◽

Chin-Lee Wu ◽

...

Keyword(s):

Extracellular Matrix ◽

Matrix Protein ◽

Extracellular Matrix Protein ◽

Β1 Integrin ◽

Thrombospondin 1

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Identification of Novel β1 Integrin Binding Sites in the Type 1 and Type 2 Repeats of Thrombospondin-1

Journal of Biological Chemistry ◽

10.1074/jbc.m406267200 ◽

2004 ◽

Vol 279 (40) ◽

pp. 41734-41743 ◽

Cited By ~ 51

Author(s):

Maria J. Calzada ◽

Douglas S. Annis ◽

Bixi Zeng ◽

Cezary Marcinkiewicz ◽

Bernhard Banas ◽

...

Keyword(s):

Binding Sites ◽

Β1 Integrin ◽

Thrombospondin 1

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Decision letter for "Nectin‐2α is localized at cholinergic neuron dendrites and regulates synapse formation in the medial habenula"

10.1002/cne.24958/v3/decision1 ◽

2020 ◽

Keyword(s):

Synapse Formation ◽

Cholinergic Neuron ◽

Medial Habenula

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Author response for "Nectin‐2α is localized at cholinergic neuron dendrites and regulates synapse formation in the medial habenula"

10.1002/cne.24958/v2/response1 ◽

2020 ◽

Author(s):

Hajime Shiotani ◽

Muneaki Miyata ◽

Takeshi Kameyama ◽

Kenji Mandai ◽

Miwako Yamasaki ◽

...

Keyword(s):

Synapse Formation ◽

Cholinergic Neuron ◽

Author Response ◽

Medial Habenula

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Cell-matrix interactions in the early mouse embryo

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100123404 ◽

1992 ◽

Vol 50 (1) ◽

pp. 600-601

Author(s):

A.E. Sutherland ◽

P.G. Calarco ◽

C.H. Damsky

Keyword(s):

Mouse Embryo ◽

Giant Cells ◽

Blastocyst Stage ◽

Integrin Subunit ◽

Β1 Integrin ◽

Cell Stage ◽

Early Mouse Embryo ◽

Migratory Activity ◽

Early Mouse ◽

Cell Matrix Interactions

Cell-extracellular matrix (ECM) interactions mediated by the integrin family of receptors are critical for morphogenesis and may also play a regulatory role in differentiation during early development. We have examined the onset of expression of individual integrin subunit proteins in the early mouse embryo, and their roles in early morphogenetic events. As detected by immunoprecipitation, the α6, αV, β1, and β3 subunits are detected as early as the 4-cell stage, α5 at the hatched blastocyst stage and αl and α3 following blastocyst attachment. We tested the role of these integrins in the attachment and migratory activity of two cell populations of the early mouse embryo: the trophoblast giant cells, which invade the uterine stroma and ultimately contribute to the chorio-allantoic placenta, and the parietal endoderm, which migrates over the inner surface of the trophoblast and ultimately forms Reichert's membrane and the parietal yolk sac. Experiments were done in serum-free medium on substrates coated with laminin (Ln) and fibronectin (Fn). Trophoblast outgrowth occurs on Ln and its E8 fragment (long arm), but not on the E1’ fragment (cross region) (Figs. 1, 2 ). This outgrowth is inhibited by anti-E8, anti-Ln, and by the anti-β1 family antiserum anti-ECMR, but not by anti-αV or the function-perturbing GoH3 antibody that recognizes the α6/β1 integrin, a major Ln (E8) receptor. This suggests that trophoblast outgrowth on Ln or E8 is mediated by a different β1 integrin such as α3/β1. Early stages of trophoblast outgrowth (up to 48 hours) on Fn are inhibited by anti-Fn and by function-perturbing anti-αV antibodies, whereas at later times outgrowth becomes insensitive to anti-αV but remains sensitive to the anti-β1 family antiserum anti-ECMr, indicating that trophoblast cells modulate their interaction with Fn during outgrowth. Trophoblast outgrowth on vitronectin (Vn) is sensitive to anti-αV antibodies throughout the 5-day period examined.

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