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Alda Tufro - One of the best experts on this subject based on the ideXlab platform.
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Semaphorins in kidney development and disease: modulators of ureteric bud branching, vascular morphogenesis, and podocyte-endothelial crosstalk
Pediatric Nephrology, 2011Co-Authors: Kimberly Reidy, Alda TufroAbstract:Semaphorins are guidance proteins that play important roles in organogenesis and disease. Expression of class 3 semaphorins and their receptors is regulated during kidney development. Gain- and loss-of-function experiments demonstrated that tight semaphorin3a gene dosage is required for podocyte differentiation, and for the establishment of a normal glomerular filtration barrier. SEMA3A modulates kidney vascular patterning acting as a negative regulator of endothelial cell migration and survival. Excess podocyte semaphorin3a expression causes glomerular disease in mice. In addition, SEMA3A is a negative regulator of ureteric bud branching, whereas Sema3c is a positive regulator of ureteric bud and endothelial cell branching morphogenesis. In summary, secreted semaphorins modulate ureteric bud branching, vascular patterning, and podocyte-endothelial crosstalk, suggesting that they play a role in renal disease. Understanding the signaling pathways downstream from semaphorin receptors will provide insight into the mechanism of action of semaphorins in renal pathology.
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Semaphorin3a inhibits ureteric bud branching morphogenesis.
Mechanisms of development, 2007Co-Authors: Alda Tufro, Jason Teichman, Craig Woda, Guillermo VillegasAbstract:Class 3 semaphorins are guidance proteins involved in axon pathfinding, vascular patterning and lung branching morphogenesis in the developing mouse embryo. Semaphorin3a (SEMA3A) is expressed in renal epithelia throughout kidney development, including podocytes and ureteric bud cells. However, the role of SEMA3A in ureteric bud branching is unknown. Here we demonstrate that SEMA3A plays a role in patterning the ureteric bud tree in both metanephric organ cultures and SEMA3A mutant mice. In vitro ureteric bud injection with SEMA3A antisense morpholino resulted in increased branching, whereas recombinant SEMA3A inhibited ureteric bud branching and decreased the number of developing glomeruli. Additional studies revealed that SEMA3A effects on ureteric bud branching involve downregulation of glial cell-line derived neurotrophic factor (GDNF) signaling, competition with vascular endothelial growth factor A (VEGF-A) and decreased activity of Akt survival pathways. Deletion of SEMA3A in mice is associated with increased ureteric bud branching, confirming its inhibitory role in vivo. Collectively, these data suggest that SEMA3A is an endogenous antagonist of ureteric bud branching and hence, plays a role in patterning the renal collecting system as a negative regulator.
Michael Klagsbrun - One of the best experts on this subject based on the ideXlab platform.
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id2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3f
Cancer Research, 2010Co-Authors: Silvia Coma, Dhara N Amin, Akio Shimizu, Anna Lasorella, Antonio Iavarone, Michael KlagsbrunAbstract:Id proteins (Id1 to Id4) are helix-loop-helix transcription factors that promote metastasis. It was found that Semaphorin 3F (SEMA3F), a potent inhibitor of metastasis, was repressed by Id2. High metastatic human tumor cell lines had relatively high amounts of Id2 and low SEMA3F levels compared with their low metastatic counterparts. No correlation between metastatic potential and expression of the other Id family members was observed. Furthermore, ectopic expression of Id2 in low metastatic tumor cells downregulated SEMA3F and, as a consequence, enhanced their ability to migrate and invade, two requisite steps of metastasis in vivo. Id2 overexpression was driven by the c-myc oncoprotein. SEMA3F was a direct target gene of the E47/Id2 pathway. Two E-box sites, which bind E protein transcription factors including E47, were identified in the promoter region of the SEMA3F gene. E47 directly activated SEMA3F promoter activity and expression and promoted SEMA3F biological activities, including filamentous actin depolymerization, inactivation of RhoA, and inhibition of cell migration. Silencing of SEMA3F inhibited the E47-induced SEMA3F expression and biological activities, confirming that these E47-induced effects were SEMA3F dependent. E47 did not induce expression of the other members of the SEMA3 family. Id2, a dominant-negative inhibitor of E proteins, abrogated the E47-induced SEMA3F expression and biological activities. Thus, high metastatic tumor cells overexpress c-myc, leading to upregulation of Id2 expression; the aberrantly elevated amount of Id2 represses SEMA3F expression and, as a consequence, enhances the ability of tumor cells to migrate and invade. Cancer Res; 70(9); 3823–32. ©2010 AACR.
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Neuropilin structure governs VEGF and semaphorin binding and regulates angiogenesis
Angiogenesis, 2008Co-Authors: Elena Geretti, Akio Shimizu, Michael KlagsbrunAbstract:Neuropilins (NRP) play a central role in neuronal and blood vessel development as receptors for two ligand types, the semaphorin (SEMA) family of axon guidance modulators and the VEGF family of angiogenesis stimulators. The role of NRPs in axon guidance is well documented but a role in blood vessel development is less so. NRPs mediate normal developmental angiogenesis as shown in mouse and zebrafish models, and pathological angiogenesis in tumors and retinal disease. The ability of two disparate ligand families to bind to the same receptor is unusual but may be explainable by analysis of neuropilin structure. There are two NRP genes, nrp1 and nrp2 . The NRPs have a relatively large extracellular domain consisting of sub domains, which are ligand binding sites. VEGF_165 binds to the b1b2 subdomain, SEMA3A and SEMA3F also bind to b1b2 but to a1a2 as well. Mutagenesis studies have identified NRP amino acids that bind VEGF_165 but not SEMA3F. These NRP structural elements might dictate differential SEMA and VEGF_165 binding properties, which in turn regulate angiogenesis. This article reviews the latest information of NRP structure and how structure influences angiogenesis. In addition, the role of NRPs in human cancer is addressed.
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Targeting endothelial and tumor cells with semaphorins
Cancer and Metastasis Reviews, 2007Co-Authors: Diane R. Bielenberg, Michael KlagsbrunAbstract:Neuropilins (NRP) are receptors for the class 3 semaphorin (SEMA3) family of axon guidance molecules and the vascular endothelial growth factor (VEGF) family of angiogenesis factors. Although the seminal studies on SEMA3s and NRPs first showed them to be mediators of axon guidance, it has become very apparent that these proteins play an important role in vascular and tumor biology as well. Neuronal guidance and angiogenesis are regulated similarly at the molecular level. For example, SEMA3s not only repel neurons and collapse axon growth cones, but have similar effects on endothelial cells and tumor cells. Preclinical studies indicate that SEMA3F is a potent inhibitor of tumor angiogenesis and metastasis. In addition, neutralizing antibodies to NRP1 enhance the effects of anti-VEGF antibodies in suppressing tumor growth in xenograft models. This article reviews NRP and SEMA3 structural interactions and their role in developmental angiogenesis, tumor angiogenesis and metastasis based on cell culture, zebrafish and murine studies.
Gera Neufeld - One of the best experts on this subject based on the ideXlab platform.
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The role of the plexin-A2 receptor in SEMA3A and Sema3B signal transduction.
Journal of Cell Science, 2014Co-Authors: Adi D. Sabag, Ofra Kessler, Tatyana Smolkin, Yelena Mumblat, Marius Ueffing, Christian Johannes Gloeckner, Gera NeufeldAbstract:Class 3 semaphorins are anti-angiogenic and anti-tumorigenic guidance factors that bind to neuropilins, which, in turn, associate with class A plexins to transduce semaphorin signals. To study the role of the plexin-A2 receptor in semaphorin signaling, we silenced its expression in endothelial cells and in glioblastoma cells. The silencing did not affect SEMA3A signaling, which depended on neuropilin-1, plexin-A1 and plexin-A4, but completely abolished Sema3B signaling, which also required plexin-A4 and one of the two neuropilins. Interestingly, overexpression of plexin-A2 in plexin-A1- or plexin-A4-silenced cells restored responses to both semaphorins, although it nullified their ability to differentiate between them, suggesting that, when overexpressed, plexin-A2 can functionally replace other class A plexins. By contrast, although plexin-A4 overexpression restored SEMA3A signaling in plexin-A1-silenced cells, it failed to restore Sema3B signaling in plexin-A2-silenced cells. It follows that the identity of plexins in functional semaphorin receptors can be flexible depending on their expression level. Our results suggest that changes in the expression of plexins induced by microenvironmental cues can trigger differential responses of different populations of migrating cells to encountered gradients of semaphorins.
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successful inhibition of tumor development by specific class 3 semaphorins is associated with expression of appropriate semaphorin receptors by tumor cells
PLOS ONE, 2008Co-Authors: Boaz Kigel, Asya Varshavsky, Ofra Kessler, Gera NeufeldAbstract:The class-3 semaphorins (sema3s) include seven family members. Six of them bind to neuropilin-1 (np1) or neuropilin-2 (np2) receptors or to both, while the seventh, sema3E, binds to the plexin-D1 receptor. Sema3B and sema3F were previously characterized as tumor suppressors and as inhibitors of tumor angiogenesis. To determine if additional class-3 semaphorins such as SEMA3A, sema3D, sema3E and sema3G possess anti-angiogenic and anti-tumorigenic properties, we expressed the recombinant full length semaphorins in four different tumorigenic cell lines expressing different combinations of class-3 semaphorin receptors. We show for the first time that SEMA3A, sema3D, sema3E and sema3G can function as potent anti-tumorigenic agents. All the semaphorins we examined were also able to reduce the concentration of tumor associated blood vessels although the potencies of the anti-angiogenic effects varied depending on the tumor cell type. Surprisingly, there was little correlation between the ability to inhibit tumor angiogenesis and their anti-tumorigenic activity. None of the semaphorins inhibited the adhesion of the tumor cells to plastic or fibronectin nor did they modulate the proliferation of tumor cells cultured in cell culture dishes. However, various semaphorins were able to inhibit the formation of soft agar colonies from tumor cells expressing appropriate semaphorin receptors, although in this case too the inhibitory effect was not always correlated with the anti-tumorigenic effect. In contrast, the anti-tumorigenic effect of each of the semaphorins correlated very well with tumor cell expression of specific signal transducing receptors for particular semaphorins. This correlation was not broken even in cases in which the tumor cells expressed significant concentrations of endogenous semaphorins. Our results suggest that combinations of different class-3 semaphorins may be more effective than single semaphorins in cases in which tumor cells express more than one type of semaphorin receptors.
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semaphorin 3b is an angiogenesis inhibitor that is inactivated by furin like pro protein convertases
Cancer Research, 2008Co-Authors: Asya Varshavsky, Boaz Kigel, Ofra Kessler, Sivan Abramovitch, Shelly Zaffryar, Gal Akiri, Gera NeufeldAbstract:Semaphorin-3B (sema3B) and semaphorin-3F (sema3F) are secreted tumor suppressors of lung cancer. Sema3F functions as an antiangiogenic factor that repels endothelial cells and compromises their proliferation/survival. However, tumor cells expressing either endogenous or recombinant sema3B fail to repel endothelial cells efficiently. Sema3B found in the conditioned medium of such cells is almost completely cleaved by furin-like pro-protein convertases, generating inactive 61- and 22-kDa fragments. We have generated a sema3B variant that was point mutated at the cleavage site (sema3B-m), thereby conferring partial resistance to cleavage. Conditioned medium from HEK293 cells expressing sema3b-m and conditioned medium of HEK293 cells expressing sema3B contained similar concentrations of semaphorin but sema3B-m was cleaved much less than sema3B. In contrast to HEK293 cells expressing native sema3B, cells expressing sema3b-m strongly repel endothelial cells. Conditioned medium from sema3B-m–expressing cells rapidly caused disassembly of focal adhesions and a collapse of the actin cytoskeleton of endothelial cells, inhibited vascular endothelial growth factor–induced phosphorylation of extracellular signal-regulated kinase 1/2, induced apoptosis of endothelial cells, and inhibited the formation of tubes from endothelial cells in an in vitro angiogenesis assay more potently than conditioned medium from cells expressing sema3B. Furthermore, HEK293 cells expressing sema3B-m inhibited basic fibroblast growth factor–induced angiogenesis in vivo much more potently than cells expressing sema3B. Repulsion of human umbilical vascular endothelial cells by sema3B-m was mediated primarily by the neuropilin-1 (np1) receptor but sema3B-m was also able to transduce signals via neuropilin-2 (np2). These results suggest that up-regulation of furin-like pro-protein convertases in malignant cells may enable tumors to evade the antiangiogenic effects of sema3B. [Cancer Res 2008;68(17):6922–31]
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semaphorin 3a and semaphorin 3f work together to repel endothelial cells and to inhibit their survival by induction of apoptosis
Journal of Biological Chemistry, 2007Co-Authors: Noga Guttmannraviv, Asya Varshavsky, Ofra Kessler, Niva Shragaheled, Cinthya Guimaraessternberg, Gera NeufeldAbstract:Abstract Semaphorin-3A (SEMA3A) is a neuropilin-1 (np1) agonist. It inhibits the binding of the 165-amino acid form of VEGF (VEGF165) to np1 and was reported to inhibit angiogenesis as a result. However, we find that SEMA3A concentrations that inhibit the mitogenic effects of VEGF165 do not inhibit VEGF165-induced phosphorylation of VEGF receptor-2 (VEGFR-2). Furthermore, SEMA3A inhibits the biological effects of VEGF121, a VEGF form that does not bind to neuropilins and basic fibroblast growth factor, a growth factor whose activity, unlike that of VEGF, is not inhibited by small interfering RNA directed against np1. Therefore, the mechanism by which SEMA3A inhibits VEGF165 activity does not depend on competition with VEGF165 for binding to np1. SEMA3A induced rapid disappearance of focal contacts followed by collapse of the actin cytoskeleton in human umbilical vein-derived endothelial cells. HEK293 cells expressing SEMA3A repel human endothelial cells and at high concentrations induce their death by apoptosis. Furthermore, SEMA3A inhibited the formation of tubes from endothelial cells in an in vitro angiogenesis assay. Similar effects are induced by the neuropilin-2 (np2) agonist sema3F. These inhibitory effects are abrogated by small interfering RNAs directed against np1 or np2, respectively. The anti-proliferative effects of SEMA3A and sema3F are additive when the semaphorins are added as pure proteins. However, when SEMA3A and sema3F were co-expressed in HEK293 cells their pro-apoptotic and cell repellant activities appeared to be synergistic. These observations suggest that combinations of SEMA3A and sema3F may be able to inhibit tumor angiogenesis more effectively than single semaphorins.
Guillermo Villegas - One of the best experts on this subject based on the ideXlab platform.
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Semaphorin3a inhibits ureteric bud branching morphogenesis.
Mechanisms of development, 2007Co-Authors: Alda Tufro, Jason Teichman, Craig Woda, Guillermo VillegasAbstract:Class 3 semaphorins are guidance proteins involved in axon pathfinding, vascular patterning and lung branching morphogenesis in the developing mouse embryo. Semaphorin3a (SEMA3A) is expressed in renal epithelia throughout kidney development, including podocytes and ureteric bud cells. However, the role of SEMA3A in ureteric bud branching is unknown. Here we demonstrate that SEMA3A plays a role in patterning the ureteric bud tree in both metanephric organ cultures and SEMA3A mutant mice. In vitro ureteric bud injection with SEMA3A antisense morpholino resulted in increased branching, whereas recombinant SEMA3A inhibited ureteric bud branching and decreased the number of developing glomeruli. Additional studies revealed that SEMA3A effects on ureteric bud branching involve downregulation of glial cell-line derived neurotrophic factor (GDNF) signaling, competition with vascular endothelial growth factor A (VEGF-A) and decreased activity of Akt survival pathways. Deletion of SEMA3A in mice is associated with increased ureteric bud branching, confirming its inhibitory role in vivo. Collectively, these data suggest that SEMA3A is an endogenous antagonist of ureteric bud branching and hence, plays a role in patterning the renal collecting system as a negative regulator.
Nicholas J P Ryba - One of the best experts on this subject based on the ideXlab platform.
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rewiring the taste system
Nature, 2017Co-Authors: Hojoon Lee, Lindsey J Macpherson, Camilo A Parada, Charles S Zuker, Nicholas J P RybaAbstract:In mammals, taste buds typically contain 50-100 tightly packed taste-receptor cells (TRCs), representing all five basic qualities: sweet, sour, bitter, salty and umami. Notably, mature taste cells have life spans of only 5-20 days and, consequently, are constantly replenished by differentiation of taste stem cells. Given the importance of establishing and maintaining appropriate connectivity between TRCs and their partner ganglion neurons (that is, ensuring that a labelled line from sweet TRCs connects to sweet neurons, bitter TRCs to bitter neurons, sour to sour, and so on), we examined how new connections are specified to retain fidelity of signal transmission. Here we show that bitter and sweet TRCs provide instructive signals to bitter and sweet target neurons via different guidance molecules (SEMA3A and SEMA7A). We demonstrate that targeted expression of SEMA3A or SEMA7A in different classes of TRCs produces peripheral taste systems with miswired sweet or bitter cells. Indeed, we engineered mice with bitter neurons that now responded to sweet tastants, sweet neurons that responded to bitter or sweet neurons responding to sour stimuli. Together, these results uncover the basic logic of the wiring of the taste system at the periphery, and illustrate how a labelled-line sensory circuit preserves signalling integrity despite rapid and stochastic turnover of receptor cells.
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Rewiring the taste system
Nature, 2017Co-Authors: Hojoon Lee, Lindsey J Macpherson, Camilo A Parada, Charles S Zuker, Nicholas J P RybaAbstract:Taste cells experience a very rapid turnover, having life spans of only 5 to 20 days, but it is not yet known how the constantly replenishing taste cells re-establish appropriate connections with their respective ganglion neurons. Here, Charles Zuker and colleagues reveal that taste receptor cells make connections with neurons representing the same taste quality based on the different axon guidance molecules expressed by each taste receptor cell type. To demonstrate this molecular logic, the authors forced a sweet taste receptor cell to establish a connection with a bitter taste quality neuron simply through the ectopic expression of the bitter guidance molecule in the sweet taste receptor cell. These findings provide insights into how the gustatory system remains organized and specific despite experiencing cell turnover on such a large scale. In mammals, taste buds typically contain 50–100 tightly packed taste-receptor cells (TRCs), representing all five basic qualities: sweet, sour, bitter, salty and umami^ 1 , 2 . Notably, mature taste cells have life spans of only 5–20 days and, consequently, are constantly replenished by differentiation of taste stem cells^ 3 . Given the importance of establishing and maintaining appropriate connectivity between TRCs and their partner ganglion neurons (that is, ensuring that a labelled line from sweet TRCs connects to sweet neurons, bitter TRCs to bitter neurons, sour to sour, and so on), we examined how new connections are specified to retain fidelity of signal transmission. Here we show that bitter and sweet TRCs provide instructive signals to bitter and sweet target neurons via different guidance molecules (SEMA3A and SEMA7A)^ 4 , 5 , 6 . We demonstrate that targeted expression of SEMA3A or SEMA7A in different classes of TRCs produces peripheral taste systems with miswired sweet or bitter cells. Indeed, we engineered mice with bitter neurons that now responded to sweet tastants, sweet neurons that responded to bitter or sweet neurons responding to sour stimuli. Together, these results uncover the basic logic of the wiring of the taste system at the periphery, and illustrate how a labelled-line sensory circuit preserves signalling integrity despite rapid and stochastic turnover of receptor cells. Taste-receptor cells use distinct semaphorins to guide wiring of the peripheral taste system; targeted ectopic expression of SEMA3A or SEMA7A leads to bitter neurons responding to sweet tastes or sweet neurons responding to bitter tastes.
