Genomes and Genes
Summary: A family of related, adhesive glycoproteins which are synthesized, secreted, and incorporated into the extracellular matrix of a variety of cells, including alpha granules of platelets following thrombin activation and endothelial cells. They interact with a number of BLOOD COAGULATION FACTORS and anticoagulant factors. Five distinct forms have been identified, thrombospondin 1, -2, -3, -4, and cartilage oligomeric matrix protein (COMP). They are involved in cell adhesion, platelet aggregation, cell proliferation, angiogenesis, tumor metastasis, VASCULAR SMOOTH MUSCLE growth, and tissue repair.
- Alford A, Terkhorn S, Reddy A, Hankenson K. Thrombospondin-2 regulates matrix mineralization in MC3T3-E1 pre-osteoblasts. Bone. 2010;46:464-71 pubmed publisher..Together, our data suggest that TSP2 may promote mineralization, by facilitating proper organization of the osteoblast-derived ECM. ..
- Liauw J, Hoang S, Choi M, Eroglu C, Choi M, Sun G, et al. Thrombospondins 1 and 2 are necessary for synaptic plasticity and functional recovery after stroke. J Cereb Blood Flow Metab. 2008;28:1722-32 pubmed publisherb>Thrombospondins 1 and 2 (TSP-1/2) belong to a family of extracellular glycoproteins with angiostatic and synaptogenic properties...
- Parma P, Radi O, Vidal V, Chaboissier M, Dellambra E, Valentini S, et al. R-spondin1 is essential in sex determination, skin differentiation and malignancy. Nat Genet. 2006;38:1304-9 pubmed..Our data show, for the first time, that disruption of a single gene can lead to complete female-to-male sex reversal in the absence of the testis-determining gene, SRY. ..
- Zhou H, Zhang H, Tang T, Zhong J, Qi Y, Luo J, et al. Alteration of thrombospondin-1 and -2 in rat brains following experimental intracerebral hemorrhage. Laboratory investigation. J Neurosurg. 2010;113:820-5 pubmed publisher..Findings in this study suggest that ICH can alter the expression of TSP-1 and TSP-2, which may be involved in modulating angiogenesis in brains following ICH. ..
- Parker H, Chase K, Cadieu E, Lark K, Ostrander E. An insertion in the RSPO2 gene correlates with improper coat in the Portuguese water dog. J Hered. 2010;101:612-7 pubmed publisher..The development of a genetic test that distinguishes these 2 allelic types would allow breeders to easily avoid producing PWD with ICs. ..
- Kopp H, Hooper A, Broekman M, Avecilla S, Petit I, Luo M, et al. Thrombospondins deployed by thrombopoietic cells determine angiogenic switch and extent of revascularization. J Clin Invest. 2006;116:3277-91 pubmed..Here, we show that expression and release of thrombospondins (TSPs) by megakaryocytes and platelets function as a major antiangiogenic switch...
- Lu W, Kim K, Liu J, Abo A, Feng X, Cao X, et al. R-spondin1 synergizes with Wnt3A in inducing osteoblast differentiation and osteoprotegerin expression. FEBS Lett. 2008;582:643-50 pubmed publisher..Finally, we demonstrated that Rspo1 synergized with Wnt3A to induce primary mouse osteoblast differentiation. Together, these findings suggest that Rpos1 may play an important role in bone remodeling. ..
- Zhao J, De Vera J, Narushima S, Beck E, Palencia S, Shinkawa P, et al. R-spondin1, a novel intestinotrophic mitogen, ameliorates experimental colitis in mice. Gastroenterology. 2007;132:1331-43 pubmed..Our results show that Rspo1 may be clinically useful in the therapeutic treatment of inflammatory bowel disease by stimulating crypt cell growth, accelerating mucosal regeneration, and restoring intestinal architecture. ..
- Hankenson K, Ausk B, Bain S, Bornstein P, Gross T, Srinivasan S. Mice lacking thrombospondin 2 show an atypical pattern of endocortical and periosteal bone formation in response to mechanical loading. Bone. 2006;38:310-6 pubmed
- Ootani A, Li X, Sangiorgi E, Ho Q, Ueno H, Toda S, et al. Sustained in vitro intestinal epithelial culture within a Wnt-dependent stem cell niche. Nat Med. 2009;15:701-6 pubmed publisher..Our results indicate successful long-term intestinal culture within a microenvironment accurately recapitulating the Wnt- and Notch-dependent ISC niche. ..
- Smith C, Shoemaker C, Roeszler K, Queen J, Crews D, Sinclair A. Cloning and expression of R-Spondin1 in different vertebrates suggests a conserved role in ovarian development. BMC Dev Biol. 2008;8:72 pubmed publisher..In all instances, RSPO1 is expressed in the incipient ovary. These findings suggest that R-SPONDIN1 is an ancient, conserved part of the vertebrate ovary-determining pathway. ..
- Frolova E, Pluskota E, Krukovets I, Burke T, Drumm C, Smith J, et al. Thrombospondin-4 regulates vascular inflammation and atherogenesis. Circ Res. 2010;107:1313-25 pubmed publisher..Our observations suggest an important role for this matricellular protein in the local regulation of inflammation associated with atherogenesis. ..
- Avouac J, Clemessy M, Distler J, Gasc J, Ruiz B, Vacher Lavenu M, et al. Enhanced expression of ephrins and thrombospondins in the dermis of patients with early diffuse systemic sclerosis: potential contribution to perturbed angiogenesis and fibrosis. Rheumatology (Oxford). 2011;50:1494-504 pubmed publisherTo determine the skin and fibroblast expression of ephrins (EphB4 and EphrinB2) and thrombospondins (TSPs: TSP1 and TSP2) in patients with SSc...
- Yoon J, Lee J. Cellular signaling and biological functions of R-spondins. Cell Signal. 2012;24:369-77 pubmed publisher..Herein, we summarize the current understanding of RSPO signaling and its biological functions, and discuss its potential therapeutic implications to human diseases. ..
- Potikyan G, Savene R, Gaulden J, France K, Zhou Z, Kleinerman E, et al. EWS/FLI1 regulates tumor angiogenesis in Ewing's sarcoma via suppression of thrombospondins. Cancer Res. 2007;67:6675-84 pubmed..Suppression of the expression of antiangiogenic factors has been closely associated with multiple malignancies. Thrombospondins 1 and 2 are members of a family of angiogenic inhibitors that are regulated by several oncogenes...
- Nam J, Park E, Turcotte T, Palencia S, Zhan X, Lee J, et al. Mouse R-spondin2 is required for apical ectodermal ridge maintenance in the hindlimb. Dev Biol. 2007;311:124-35 pubmed..Our findings strongly suggest that Rspo2 expression in the AER is required for AER maintenance likely by regulating Wnt/beta-catenin signaling. ..
- Blaydon D, Ishii Y, O Toole E, Unsworth H, Teh M, Ruschendorf F, et al. The gene encoding R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signaling, is mutated in inherited anonychia. Nat Genet. 2006;38:1245-7 pubmed..Rspo4 expression was specifically localized to developing mouse nail mesenchyme at embryonic day 15.5, suggesting a crucial role in nail morphogenesis. ..
- Friedman M, Oyserman S, Hankenson K. Wnt11 promotes osteoblast maturation and mineralization through R-spondin 2. J Biol Chem. 2009;284:14117-25 pubmed publisher..These studies show that Wnt11 signals through beta-catenin, activating Rspo2 expression, which is then required for Wnt11-mediated osteoblast maturation. ..
- Meng H, Zhang X, Hankenson K, Wang M. Thrombospondin 2 potentiates notch3/jagged1 signaling. J Biol Chem. 2009;284:7866-74 pubmed publisherExtracellular thrombospondins (TSP or THBS) and the Notch family of transmembrane receptors share a role in multiple, overlapping cellular functions and participate in developmental signaling and pathological reactions to tissue injury...
- Chadi S, Buscara L, Pechoux C, Costa J, Laubier J, Chaboissier M, et al. R-spondin1 is required for normal epithelial morphogenesis during mammary gland development. Biochem Biophys Res Commun. 2009;390:1040-3 pubmed publisher..Our data demonstrate that local epithelial Rspo1 signalling is required for normal development of the mammary gland. ..
- Kazanskaya O, Ohkawara B, Heroult M, Wu W, Maltry N, Augustin H, et al. The Wnt signaling regulator R-spondin 3 promotes angioblast and vascular development. Development. 2008;135:3655-64 pubmed publisher..We show that vascular endothelial growth factor is an immediate early response gene and a mediator of R-spondin signaling. The results identify Rspo3 as a novel, evolutionarily conserved angiogenic factor in embryogenesis. ..
- Aoki M, Mieda M, Ikeda T, Hamada Y, Nakamura H, Okamoto H. R-spondin3 is required for mouse placental development. Dev Biol. 2007;301:218-26 pubmed..These findings suggest a critical role for Rspo3 in the interaction between chorion and allantois in labyrinthine development. ..
- Kocer A, Pinheiro I, Pannetier M, Renault L, Parma P, Radi O, et al. R-spondin1 and FOXL2 act into two distinct cellular types during goat ovarian differentiation. BMC Dev Biol. 2008;8:36 pubmed publisher..Moreover, our data suggest that RSPO1 may be associated with germ cell development and meiosis. Interestingly, another RSPO gene, RSPO2 shows a sex-dimorphic pattern of expression that is dramatically influenced by the PIS mutation. ..
- Kim D, Li K, Boroujerdi A, Peter Yu Y, Zhou C, Deng P, et al. Thrombospondin-4 contributes to spinal sensitization and neuropathic pain states. J Neurosci. 2012;32:8977-87 pubmed publisher..Development of TSP4 antagonists has the therapeutic potential for target-specific neuropathic pain management. ..
- Bergmann C, Senderek J, Anhuf D, Thiel C, Ekici A, Poblete Gutierrez P, et al. Mutations in the gene encoding the Wnt-signaling component R-spondin 4 (RSPO4) cause autosomal recessive anonychia. Am J Hum Genet. 2006;79:1105-9 pubmed..To the best of our knowledge, this is the first gene known to be responsible for an isolated, nonsyndromic nail disorder. ..
- Risher W, Eroglu C. Thrombospondins as key regulators of synaptogenesis in the central nervous system. Matrix Biol. 2012;31:170-7 pubmed publisherb>Thrombospondins (TSPs) are a family of large, oligomeric multidomain glycoproteins that participate in a variety of biological functions as part of the extracellular matrix (ECM)...
- Wilhelm D. R-spondin1--discovery of the long-missing, mammalian female-determining gene?. Bioessays. 2007;29:314-8 pubmed..In this review, possible roles of R-spondin1 during sex determination as well as questions arising from this study will be discussed. ..
- Hankenson K, Sweetwyne M, Shitaye H, Posey K. Thrombospondins and novel TSR-containing proteins, R-spondins, regulate bone formation and remodeling. Curr Osteoporos Rep. 2010;8:68-76 pubmed publisherb>Thrombospondins (TSPs) are a family of five secreted multimeric matricellular proteins that share homology in the type II and III repeats and carboxy-terminal region...
- Ruffner H, Sprunger J, Charlat O, Leighton Davies J, Grosshans B, Salathe A, et al. R-Spondin potentiates Wnt/?-catenin signaling through orphan receptors LGR4 and LGR5. PLoS ONE. 2012;7:e40976 pubmed publisher..Identification of LGR4 and its relative LGR5, an adult stem cell marker, as the receptors of RSPO will facilitate the further characterization of these receptor/ligand pairs in regenerative medicine applications. ..
- Bhanja P, Saha S, Kabarriti R, Liu L, Roy Chowdhury N, Roy Chowdhury J, et al. Protective role of R-spondin1, an intestinal stem cell growth factor, against radiation-induced gastrointestinal syndrome in mice. PLoS ONE. 2009;4:e8014 pubmed publisher..Rspo1 has protective effect only on normal intestinal tissue but not in tumors after AIR and thereby may increase the therapeutic ratio of chemoradiation therapy in patients undergoing abdominal irradiation for GI malignancies. ..
- Takashima S, Kadowaki M, Aoyama K, Koyama M, Oshima T, Tomizuka K, et al. The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells. J Exp Med. 2011;208:285-94 pubmed publisher..Our results demonstrate for the first time that ISC damage plays a central role in amplifying systemic GVHD; therefore, we propose ISC protection by R-Spo1 as a novel strategy to improve the outcome of allogeneic BMT. ..
- Wolfstetter G, Holz A. The role of LamininB2 (LanB2) during mesoderm differentiation in Drosophila. Cell Mol Life Sci. 2012;69:267-82 pubmed publisher..We also observed genetic interactions with kon-tiki and thrombospondin, indicating a role for laminin during muscle attachment. ..
- Zhou L, Charkraborty T, Yu X, Wu L, Liu G, Mohapatra S, et al. R-spondins are involved in the ovarian differentiation in a teleost, medaka (Oryzias latipes). BMC Dev Biol. 2012;12:36 pubmed publisher..These results suggest that the Rspo-activating signaling pathway is involved in the ovarian differentiation and maintenance in medaka...
- Kim K, Zhao J, Andarmani S, Kakitani M, Oshima T, Binnerts M, et al. R-Spondin proteins: a novel link to beta-catenin activation. Cell Cycle. 2006;5:23-6 pubmed
- Chassot A, Gregoire E, Magliano M, Lavery R, Chaboissier M. Genetics of ovarian differentiation: Rspo1, a major player. Sex Dev. 2008;2:219-27 pubmed publisher..A particular focus will be on Rspo1 and its crucial function in sex determination. ..
- Chatila K, Ren G, Xia Y, Huebener P, Bujak M, Frangogiannis N. The role of the thrombospondins in healing myocardial infarcts. Cardiovasc Hematol Agents Med Chem. 2007;5:21-7 pubmed..Understanding the specific mechanisms responsible for the protective effects of TSP-1 and TSP-2 in healing infarcts may lead to novel therapeutic interventions aiming at attenuating adverse left ventricular remodeling. ..
- Bell S, Schreiner C, Wert S, Mucenski M, Scott W, Whitsett J. R-spondin 2 is required for normal laryngeal-tracheal, lung and limb morphogenesis. Development. 2008;135:1049-58 pubmed publisher..Interbreeding the Rspo2(Tg) and Lrp6(-) alleles resulted in more severe defects consisting of marked lung hypoplasia and absence of tracheal-bronchial rings, laryngeal structures and all limb skeletal elements. ..
- Nam J, Turcotte T, Smith P, Choi S, Yoon J. Mouse cristin/R-spondin family proteins are novel ligands for the Frizzled 8 and LRP6 receptors and activate beta-catenin-dependent gene expression. J Biol Chem. 2006;281:13247-57 pubmed..Our findings expand the repertoire of ligands that induce beta-catenin/TCF-dependent gene activation and implicate the presence of active beta-catenin-dependent gene activation in a Wnt-free biological context. ..
- Tomaselli S, Megiorni F, De Bernardo C, Felici A, Marrocco G, Maggiulli G, et al. Syndromic true hermaphroditism due to an R-spondin1 (RSPO1) homozygous mutation. Hum Mutat. 2008;29:220-6 pubmed..The reported findings represent a further step toward a complete understanding of the complex mechanisms leading to DSDs. ..
- Aoki M, Kiyonari H, Nakamura H, Okamoto H. R-spondin2 expression in the apical ectodermal ridge is essential for outgrowth and patterning in mouse limb development. Dev Growth Differ. 2008;50:85-95 pubmed..This study shows that Rspo2 is critical for maintenance of the AER and for growth and patterning in limb development. ..
- Oganesian A, Armstrong L, Migliorini M, Strickland D, Bornstein P. Thrombospondins use the VLDL receptor and a nonapoptotic pathway to inhibit cell division in microvascular endothelial cells. Mol Biol Cell. 2008;19:563-71 pubmedTSPs 1 and 2 function as endogenous inhibitors of angiogenesis. Although thrombospondins (TSPs) have been shown to induce apoptosis in HMVECs, we reasoned that a homeostatic mechanism would also be needed to inhibit EC growth without ..
- Tomaselli S, Megiorni F, Lin L, Mazzilli M, Gerrelli D, Majore S, et al. Human RSPO1/R-spondin1 is expressed during early ovary development and augments Î²-catenin signaling. PLoS ONE. 2011;6:e16366 pubmed publisher..Taken together, these data show that R-spondin1 is upregulated during critical stages of early human ovary development and may function as a tissue-specific amplifier of Î²-catenin signaling to oppose testis determination. ..
- Nishiwaki T, Yamaguchi T, Zhao C, Amano H, Hankenson K, Bornstein P, et al. Reduced expression of thrombospondins and craniofacial dysmorphism in mice overexpressing Fra1. J Bone Miner Res. 2006;21:596-604 pubmed..Therefore, reduced expression of thrombospondins may contribute to craniofacial dysmorphism independently of osteosclerosis...
- Hao H, Xie Y, Zhang Y, Charlat O, Oster E, Avello M, et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature. 2012;485:195-200 pubmed publisher..These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3. Our study provides new mechanistic insights into the regulation of Wnt receptor turnover, and reveals ZNRF3 as a tractable target for therapeutic exploration...
- Brüchle N, Frank J, Frank V, Senderek J, Akar A, Koc E, et al. RSPO4 is the major gene in autosomal-recessive anonychia and mutations cluster in the furin-like cysteine-rich domains of the Wnt signaling ligand R-spondin 4. J Invest Dermatol. 2008;128:791-6 pubmed
- Haakensen V, Bjøro T, Lüders T, Riis M, Bukholm I, Kristensen V, et al. Serum estradiol levels associated with specific gene expression patterns in normal breast tissue and in breast carcinomas. BMC Cancer. 2011;11:332 pubmed publisher..PTGS1 induces prostaglandin E2 (PGE2) production which in turn stimulates aromatase expression and hence increases the local production of estradiol. This is the first report studying such associations in normal breast tissue in humans. ..
- Huch M, Dorrell C, Boj S, van Es J, Li V, van de Wetering M, et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature. 2013;494:247-50 pubmed publisher..These findings indicate that previous observations concerning Lgr5(+) stem cells in actively self-renewing tissues can also be extended to damage-induced stem cells in a tissue with a low rate of spontaneous proliferation...
- Huang J, Zhou L, Wang H, Luo J, Zeng L, Xiong K, et al. Distribution of thrombospondins and their neuronal receptor ?2?1 in the rat retina. Exp Eye Res. 2013;111:36-49 pubmed publisherThe role of the extracellular matrix protein thrombospondins (TSPs) in promoting synaptogenesis is gaining more and more attention...
- Kim K, Wagle M, Tran K, Zhan X, Dixon M, Liu S, et al. R-Spondin family members regulate the Wnt pathway by a common mechanism. Mol Biol Cell. 2008;19:2588-96 pubmed publisher..Together, these findings indicate that RSpo proteins modulate the Wnt pathway by a common mechanism and suggest that coexpression with specific Wnt ligands and DKK1 may determine their biological specificity in vivo. ..
- Mathew L, Sengupta S, Ladu J, Andreasen E, Tanguay R. Crosstalk between AHR and Wnt signaling through R-Spondin1 impairs tissue regeneration in zebrafish. FASEB J. 2008;22:3087-96 pubmed publisher..Collectively, these results indicate that inappropriate regulation of R-Spondin/LRP6 is absolutely required for TCDD to inhibit fin regeneration. ..
- Wang C, Su P, Du X, Kuo M, Lin C, Yang C, et al. Thrombospondin type I domain containing 7A (THSD7A) mediates endothelial cell migration and tube formation. J Cell Physiol. 2010;222:685-94 pubmed publisher..Our results show that THSD7A is a novel placenta endothelial protein that mediates EC migration and tube formation, and they highlight its potential as a new target for anti-angiogenic therapy. ..
- Liu A, Garg P, Yang S, Gong P, Pallero M, Annis D, et al. Epidermal growth factor-like repeats of thrombospondins activate phospholipase Cgamma and increase epithelial cell migration through indirect epidermal growth factor receptor activation. J Biol Chem. 2009;284:6389-402 pubmed publisher..Access to the ligand-binding portion of the EGFR ectodomain was also required. These findings suggest release of an endogenous EGFR ligand in response to ligation of a second unknown receptor by the TSPs. ..
- Wang C, Chen I, Kuo M, Su P, Lai Z, Wang C, et al. Zebrafish Thsd7a is a neural protein required for angiogenic patterning during development. Dev Dyn. 2011;240:1412-21 pubmed publisher..Collectively, our study shows that zebrafish Thsd7a is a neural protein required for ISV angiogenesis, and suggests an important role of Thsd7a in the neurovascular interaction during zebrafish development. ..
- Wang D, Huang B, Zhang S, Yu X, Wu W, Wang X. Structural basis for R-spondin recognition by LGR4/5/6 receptors. Genes Dev. 2013;27:1339-44 pubmed publisher..Our results define the molecular mechanism by which the LGR4/5/6 receptors recognize RSPOs and also provide structural insights into the signaling difference between the LGR4/5/6 receptors and other members in the LGR family. ..
- Gruber H, Ingram J, Hanley E. Immunolocalization of thrombospondin in the human and sand rat intervertebral disc. Spine (Phila Pa 1976). 2006;31:2556-61 pubmed..Since TSP has recognized antiangiogenic effects both in vitro and in vivo, we suggest that the strong immunolocalization of TSP in the outer anulus indicates a role for TSP in the avascular status of the adult human and sand rat disc. ..
- de Lau W, Barker N, Low T, Koo B, Li V, Teunissen H, et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature. 2011;476:293-7 pubmed publisher..These results will guide future studies towards the application of R-spondins for regenerative purposes of tissues expressing Lgr5 homologues. ..
- Carmon K, Gong X, Lin Q, Thomas A, Liu Q. R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Proc Natl Acad Sci U S A. 2011;108:11452-7 pubmed publisher..The findings provide a basis for stem cell-specific effects of Wnt/?-catenin signaling and for the broad range of functions LGR4, LGR5, and the R-spondins have in normal and malignant growth. ..
- Cadieu E, Neff M, Quignon P, Walsh K, Chase K, Parker H, et al. Coat variation in the domestic dog is governed by variants in three genes. Science. 2009;326:150-3 pubmed publisher..Thus, an array of varied and seemingly complex phenotypes can be reduced to the combinatorial effects of only a few genes. ..
- Chassot A, Ranc F, Gregoire E, Roepers Gajadien H, Taketo M, Camerino G, et al. Activation of beta-catenin signaling by Rspo1 controls differentiation of the mammalian ovary. Hum Mol Genet. 2008;17:1264-77 pubmed publisher..Thus, a balance between Sox9 and beta-catenin activation determines the fate of the gonad, with Rspo1 acting as a crucial regulator of canonical beta-catenin signaling required for female development. ..
- Tan K, Duquette M, Joachimiak A, Lawler J. The crystal structure of the signature domain of cartilage oligomeric matrix protein: implications for collagen, glycosaminoglycan and integrin binding. FASEB J. 2009;23:2490-501 pubmed publisher..The structure presented here and its unique molecular packing in the crystal identify potential interactive sites for glycosaminoglycans, integrins, and collagens, which are key to cartilage structure and function. ..