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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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Neuropilin 1 vegfr 2 complexing requires the pdz binding domain of Neuropilin 1
Journal of Biological Chemistry, 2008Co-Authors: Claudia Prahst, Ofra Kessler, Niva Shragaheled, Gera Neufeld, Melanie Heroult, Anthony A Lanahan, Noa Uziel, Michael Simons, Hellmut G AugustinAbstract:Vascular endothelial growth factor (VEGF) acts as a hierarchically high switch of the angiogenic cascade by interacting with its high affinity VEGF receptors and with Neuropilin co-receptors. VEGF165 binds to both Neuropilin-1 (NP-1) and VEGFR-2, and it is believed that ligand binding forms an extracellular bridge between both molecules. This leads to complex formation, thereby enhancing VEGFR-2 phosphorylation and subsequent signaling. We found that inhibition of VEGF receptor (VEGFR) phosphorylation reduced complex formation between NP-1 and VEGFR-2, suggesting a functional role of the cytoplasmic domain of VEGFR-2 for complex formation. Correspondingly, deleting the PDZ-binding domain of NP-1 decreased complex formation, indicating that extracellular VEGF165 binding is not sufficient for VEGFR-2-NP-1 interaction. Synectin is an NP-1 PDZ-binding domain-interacting molecule. Experiments in Synectin-deficient endothelial cells revealed reduced VEGFR-2-NP-1 complex formation, suggesting a role for Synectin in VEGFR-2-NP-1 signaling. Taken together, the experiments have identified a novel mechanism of NP-1 interaction with VEGFR-2, which involves the cytoplasmic domain of NP-1.
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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, Ofra Kessler, Asya Varshavsky, 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.
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segregation of arterial and venous markers in subpopulations of blood islands before vessel formation
Developmental Dynamics, 2005Co-Authors: Yael Herzog, Noga Guttmannraviv, Gera NeufeldAbstract:The Neuropilin-1 (np1) and the Neuropilin-2 (np2) receptors bind vascular endothelial growth factor (VEGF) and class-3 semaphorins. They form complexes with VEGF tyrosine-kinase receptors or alternatively with type-A plexins to transduce respective VEGF or semaphorin signals. We have compared the expression patterns of np1, np2, plexin-A1, and plexin-A2 in the emerging vasculature of chick embryos. Double in situ hybridization reveals that six-somite embryos contain intermingled extraembryonic blood island (BI) subpopulations that express np1 or np2 as well as a BI subpopulation that coexpresses both Neuropilins. In 13-somite embryos, which already contain an extraembryonic vascular plexus, the expression of np1 and np2 is segregated between the arterial and venous parts of the plexus, despite the absence of blood flow. However, the arterial marker ephrin-B2 was not yet expressed in the plexus at this stage. In 26-somite embryos, which possess a functional vascular system, np1 and np2 are differentially expressed in arteries and veins as previously reported. At this stage, posterior BIs expressing np2 appear to undergo fusion to form the posterior sinus vein and its tributaries, suggesting that the venous identity of these veins may be established before their formation. The Neuropilin coreceptor plexin-A2 was expressed in extraembryonic veins but not in extraembryonic arteries. In contrast, within the embryo, plexin-A2 expression was observed in the dorsal aorta as well as in the cardinal vein. Semaphorin-3F (s3f), an np2 ligand, bound to np2-expressing cells in 26-somite embryos regardless of the presence or absence of plexin-A1 or plexin-A2. Of interest, even though s3f binds to np1 in vitro, np1-expressing arteries fail to bind s3f in whole-mount binding experiments. Developmental Dynamics 232:1047–1055, 2005. © 2005 Wiley-Liss, Inc.
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the Neuropilins multifunctional semaphorin and vegf receptors that modulate axon guidance and angiogenesis
Trends in Cardiovascular Medicine, 2002Co-Authors: Gera NeufeldAbstract:The Neuropilin-1 (np1) and Neuropilin-2 (np2) receptors function as receptors for the axon guidance factors belonging to the class-3 semaphorin subfamily. In addition, both Neuropilins are able to bind to certain heparin-binding splice forms of vascular endothelial growth factor (VEGF), indicating that both Neuropilins have roles in the cardiovascular system as well. Gene targeting experiments indicate that np1 does indeed function as an important modulator of VEGF function during vasculogenesis and angiogenesis, but the role of np2 in the cardiovascular system has not been studied in detail as yet. This review focuses on the Neuropilins, their interactions, and their biological roles in the nervous and cardiovascular systems.
Michael Klagsbrun - One of the best experts on this subject based on the ideXlab platform.
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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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Neuropilins in neoplasms: expression, regulation, and function.
Experimental cell research, 2006Co-Authors: Diane R. Bielenberg, Curtis A. Pettaway, Seiji Takashima, Michael KlagsbrunAbstract:Neuropilins (NRP) are membranous receptors capable of binding two disparate ligands, class 3 semaphorins (SEMA) and vascular endothelial growth factors (VEGF), and regulating two diverse systems, neuronal guidance and angiogenesis. The Neuropilin genes, NRP1 and NRP2, share similar protein structure, but differ in their expression patterns, regulation, and ligand-binding specificities. NRPs vary in their expression patterns; for example, endothelial cells express both NRP1 and NRP2, lymphatic endothelial cells predominantly express NRP2, and epidermal cells predominantly express NRP1. NRP expression can be differentially regulated by transcription factors, e.g. prox-1 induces NRP2 while suppressing NRP1, or by growth factors, e.g. epidermal growth factor (EGF) induces NRP1 but not NRP2. Nearly all tumor cells express NRP1, NRP2, or both. Carcinomas express NRP1, whereas neuronal tumors and melanomas predominantly express NRP2. SEMAs play a role in neoplasms as angiogenesis inhibitors. For example, SEMA3F, which binds specifically to NRP2, inhibits tumor angiogenesis and metastasis. Metastatic tumor cells lose SEMA3F expression during progression. Therefore, SEMA3F may have therapeutic potential. This article focuses on the role of NRPs and SEMAs in tumor progression and angiogenesis.
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overexpression of Neuropilin 1 promotes constitutive mapk signalling and chemoresistance in pancreatic cancer cells
British Journal of Cancer, 2005Co-Authors: Jane S Wey, Michael J Gray, Fan Fan, Anna Belcheva, Marya F Mccarty, Oliver Stoeltzing, Ray Somcio, Wenbiao Liu, Douglas B Evans, Michael KlagsbrunAbstract:Neuropilin-1 (NRP-1) is a novel co-receptor for vascular endothelial growth factor (VEGF). Neuropilin-1 is expressed in pancreatic cancer, but not in nonmalignant pancreatic tissue. We hypothesised that NRP-1 expression by pancreatic cancer cells contributes to the malignant phenotype. To determine the role of NRP-1 in pancreatic cancer, NRP-1 was stably transfected into the human pancreatic cancer cell line FG. Signal transduction was assessed by Western blot analysis. Susceptibility to anoikis (detachment induced apoptosis) was evaluated by colony formation after growth in suspension. Chemosensitivity to gemcitabine or 5-fluorouracil (5-FU) was assessed by MTT assay in pancreatic cancer cells following NRP-1 overexpression or siRNA-induced downregulation of NRP-1. Differential expression of apoptosis-related genes was determined by gene array and further evaluated by Western blot analysis. Neuropilin-1 overexpression increased constitutive mitogen activated protein kinase (MAPK) signalling, possibly via an autocrine loop. Neuropilin-1 overexpression in FG cells enhanced anoikis resistance and increased survival of cells by >30% after exposure to clinically relevant levels of gemcitabine and 5-FU. In contrast, downregulation of NRP-1 expression in Panc-1 cells markedly increased chemosensitivity, inducing >50% more cell death at clinically relevant concentrations of gemcitabine. Neuropilin-1 overexpression also increased expression of the antiapoptotic regulator, MCL-1. Neuropilin-1 overexpression in pancreatic cancer cell lines is associated with (a) increased constitutive MAPK signalling, (b) inhibition of anoikis, and (c) chemoresistance. Targeting NRP-1 in pancreatic cancer cells may downregulate survival signalling pathways and increase sensitivity to chemotherapy.
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expression and mapping of duplicate Neuropilin 1 and Neuropilin 2 genes in developing zebrafish
Gene Expression Patterns, 2004Co-Authors: Diane E Bovenkamp, Katsutoshi Goishi, Nathan Bahary, Alan J Davidson, Yi Zhou, Thomas Becker, Catherina G Becker, Leonard I Zon, Michael KlagsbrunAbstract:Previously, we described the isolation and characterization of the first zebrafish Neuropilin gene, which we now call nrp1a, and found its protein to be a mediator of vascular endothelial growth factor (VEGF)-dependent angiogenesis [Proc. Natl Acad. Sci. USA 99 (2002) 10470]. Subsequently, we have isolated three other full-length Neuropilin genes (nrp1b, nrp2a, and nrp2b) and find that they map to independent zebrafish linkage groups. The nrp1s and nrp2s had differential spatio-temporal gene expression profiles with nrp1a being most prominent in the gut, brain, retina, hypochord, motorneurons, fin bud and mandibular cartilage, nrp1b in the brain, dorsal aorta, melanophores, ventral fin, and heart, nrp2a in the brain, retina, heart, and caudal vessels, and nrp2b in the brain, retina, gut, fin bud, melanophores, heart, and caudal vessels. In addition, we have identified an alternatively-spliced transcript of the nrp1b gene (denoted as nrp1b(s)) which is predicted to encode a soluble form of Nrp1b, containing only the a, b, and c extracellular domains. Transcript expression of nrp1b(s) was different from full-length nrp1b transcript, with prominence in the brain, developing mouth, heart, and fin bud. The NRP1s were tested for VEGF-binding ability. Both 125 kDa Nrp1a and 145 kDa Nrp1b bound 125I-labelled VEGFA165. In summary, two nrp1 and two nrp2 genes, with expression patterns similar to higher vertebrates, have been isolated from zebrafish.
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Neuropilin 1 is expressed by endothelial and tumor cells as an isoform specific receptor for vascular endothelial growth factor
Cell, 1998Co-Authors: Shay Soker, Gera Neufeld, Seiji Takashima, Hua Quan Miao, Michael KlagsbrunAbstract:Vascular endothelial growth factor (VEGF), a major regulator of angiogenesis, binds to two receptor tyrosine kinases, KDR/Flk-1 and Flt-1. We now describe the purification and the expression cloning from tumor cells of a third VEGF receptor, one that binds VEGF165 but not VEGF121. This isoform-specific VEGF receptor (VEGF165R) is identical to human Neuropilin-1, a receptor for the collapsin/semaphorin family that mediates neuronal cell guidance. When coexpressed in cells with KDR, Neuropilin-1 enhances the binding of VEGF165 to KDR and VEGF165-mediated chemotaxis. Conversely, inhibition of VEGF165 binding to Neuropilin-1 inhibits its binding to KDR and its mitogenic activity for endothelial cells. We propose that Neuropilin-1 is a novel VEGF receptor that modulates VEGF binding to KDR and subsequent bioactivity and therefore may regulate VEGF-induced angiogenesis.
Anil Bagri - One of the best experts on this subject based on the ideXlab platform.
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Neuropilins as semaphorin receptors in vivo functions in neuronal cell migration and axon guidance
Advances in Experimental Medicine and Biology, 2002Co-Authors: Anil BagriAbstract:After the initial discovery of Neuropilin-1 as an epitope on axons recognized by a monoclonal antibody, Neuropilins were rediscovered in the search for receptors mediating the repulsive actions of class 3 Semaphorins, notably Sema3A. Neuropilins are the ligand binding moieties in the class 3 Semaphorin receptor complexes, with the signaling moieties apparently provided by members of the plexin family. In their capacity as Semaphorin receptors, Neuropilins have been shown to transduce repulsive guidance signals that direct a large variety of cell migration and axon guidance events. We summarize their demonstrated roles in driving axon fasciculation, channeling various axonal populations, inhibiting axonal branching, creating exclusion zones for axons, and providing directional guidance cues by being presented in gradients. In addition to their roles in repulsive axon guidance, evidence is accumulating that Neuropilins also transduce some attractive guidance functions of Semaphorins.
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Sorting of Striatal and Cortical Interneurons Regulated by Semaphorin-Neuropilin Interactions
Science (New York N.Y.), 2001Co-Authors: Oscar Marín, Anil Bagri, Marc Tessier-lavigne, Avraham Yaron, John L.r. RubensteinAbstract:Most striatal and cortical interneurons arise from the basal telencephalon, later segregating to their respective targets. Here, we show that migrating cortical interneurons avoid entering the striatum because of a chemorepulsive signal composed at least in part of semaphorin 3A and semaphorin 3F. Migrating interneurons expressing Neuropilins, receptors for semaphorins, are directed to the cortex; those lacking them go to the striatum. Loss of Neuropilin function increases the number of interneurons that migrate into the striatum. These observations reveal a mechanism by which Neuropilins mediate sorting of distinct neuronal populations into different brain structures, and provide evidence that, in addition to guiding axons, these receptors also control neuronal migration in the central nervous system.
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Neuropilin 2 regulates the development of select cranial and sensory nerves and hippocampal mossy fiber projections
Neuron, 2000Co-Authors: Hang Chen, Anil Bagri, Joel Zupicich, Yimin Zou, Esther T Stoeckli, Samuel J Pleasure, Daniel H Lowenstein, William C Skarnes, Alain ChedotalAbstract:Neuropilin-1 and Neuropilin-2 bind differentially to different class 3 semaphorins and are thought to provide the ligand-binding moieties in receptor complexes mediating repulsive responses to these semaphorins. Here, we have studied the function of Neuropilin-2 through analysis of a Neuropilin-2 mutant mouse, which is viable and fertile. Repulsive responses of sympathetic and hippocampal neurons to Sema3F but not to Sema3A are abolished in the mutant. Marked defects are observed in the development of several cranial nerves, in the initial central projections of spinal sensory axons, and in the anterior commissure, habenulo-interpeduncular tract, and the projections of hippocampal mossyfiber axons in the infrapyramidal bundle. Our results show that Neuropilin-2 is an essential component of the Sema3F receptor and identify key roles for Neuropilin-2 in axon guidance in the PNS and CNS.
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semaphorin Neuropilin interactions underlying sympathetic axon responses to class iii semaphorins
Neuron, 1998Co-Authors: Hang Chen, Anil BagriAbstract:Neuropilin-1 and Neuropilin-2 show specificity in binding to different class III semaphorins, including Sema III, Sema E, and Sema IV, suggesting that the specificity of action of these semaphorins is dictated by the complement of Neuropilins expressed by responsive neurons. In support of this, we show that sympathetic axons coexpress Neuropilin-1 and -2, that their responses to Sema III, Sema E, and Sema IV are affected in predicted ways by antibodies to Neuropilin-1, and that Neuropilin-1 and -2 can form homo- and heterooligomers through an interaction involving at least partly the Neuropilin MAM (meprin, A5, mu) domain. These results support the idea that in sympathetic axons, the Sema III signal is mediated predominantly by Neuropilin-1 oligomers, the Sema IV signal by Neuropilin-2 oligomers, and the Sema E signal by Neuropilin-1 and -2, either as homo- or heterooligomers.
Roman J. Giger - One of the best experts on this subject based on the ideXlab platform.
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Neuropilin 2 mediates axonal fasciculation zonal segregation but not axonal convergence of primary accessory olfactory neurons
Neuron, 2002Co-Authors: Jeanfrancois Cloutier, Roman J. Giger, Alex L. Kolodkin, Georgy Koentges, Catherine Dulac, David D. GintyAbstract:The mechanisms that underlie axonal pathfinding of vomeronasal neurons from the vomeronasal organ (VNO) in the periphery to select glomeruli in the accessory olfactory bulb (AOB) are not well understood. Neuropilin-2, a receptor for secreted semaphorins, is expressed in V1R- and V3R-expressing, but not V2R-expressing, postnatal vomeronasal neurons. Analysis of the vomeronasal nerve in Neuropilin-2 (npn-2) mutant mice reveals pathfinding defects at multiple choice points. Vomeronasal sensory axons are severely defasciculated and a subset innervates the main olfactory bulb (MOB). While most axons of V1R-expressing neurons reach the AOB and converge into distinct glomeruli in stereotypic locations, they are no longer restricted to their normal anterior AOB target zone. Thus, Npn-2 and candidate pheromone receptors play distinct and complementary roles in promoting the wiring and patterning of sensory neurons in the accessory olfactory system.
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Neuropilin 2 is required in vivo for selective axon guidance responses to secreted semaphorins
Neuron, 2000Co-Authors: Roman J. Giger, Dorothy V. Levengood, Jeanfrancois Cloutier, Amar Sahay, Rab K Prinjha, Stephen E Moore, Susan J Pickering, David Simmons, Sohaila Rastan, Frank S WalshAbstract:Neuropilins are receptors for class 3 secreted semaphorins, most of which can function as potent repulsive axon guidance cues. We have generated mice with a targeted deletion in the Neuropilin-2 (Npn-2) locus. Many Npn-2 mutant mice are viable into adulthood, allowing us to assess the role of Npn-2 in axon guidance events throughout neural development. Npn-2 is required for the organization and fasciculation of several cranial nerves and spinal nerves. In addition, several major fiber tracts in the brains of adult mutant mice are either severely disorganized or missing. Our results show that Npn-2 is a selective receptor for class 3 semaphorins in vivo and that Npn-1 and Npn-2 are required for development of an overlapping but distinct set of CNS and PNS projections.
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expression of the gene encoding the chemorepellent semaphorin iii is induced in the fibroblast component of neural scar tissue formed following injuries of adult but not neonatal cns
Molecular and Cellular Neuroscience, 1999Co-Authors: R J Pasterkamp, Roman J. Giger, Marc J Ruitenberg, A J G D Holtmaat, F De Winter, Joost VerhaagenAbstract:This study evaluates the expression of the chemorepellent semaphorin III (D)/collapsin-1 (sema III) following lesions to the rat CNS. Scar tissue, formed after penetrating injuries to the lateral olfactory tract (LOT), cortex, perforant pathway, and spinal cord, contained numerous spindle-shaped cells expressing high levels of sema III mRNA. The properties of these cells were investigated in detail in the lesioned LOT. Most sema III mRNA-positive cells were located in the core of the scar and expressed proteins characteristic for fibroblast-like cells. Neuropilin-1, a sema III receptor, was expressed in injured neurons with projections to the lesion site, in a subpopulation of scar-associated cells and in blood vessels around the scar. In contrast to lesions made in the mature CNS, LOT transection in neonates did not induce sema III mRNA expression within cells in the lesion and was followed by vigorous axonal regeneration. The concomitant expression of sema III and its receptor Neuropilin-1 in the scar suggests that sema III/Neuropilin-1-mediated mechanisms are involved in CNS scar formation. The expression of the secreted chemorepellent sema III following CNS injury provides the first evidence that chemorepulsive semaphorins may contribute to the inhibitory effects exerted by scars on the outgrowth of injured CNS neurites. The vigorous regrowth of injured axons in the absence of sema III following early neonatal lesions is consistent with this notion. The inactivation of sema III in scar tissue by either antibody perturbation or by genetic or pharmacological intervention could be a powerful means to promote long-distance regeneration in the adult CNS.
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Neuropilin-2 Is a Receptor for Semaphorin IV Insight into the Structural Basis of Receptor Function and Specificity
Neuron, 1998Co-Authors: Roman J. Giger, Erica Rowe Urquhart, Susan K.h Gillespie, Dorothy V. Levengood, David D. Ginty, Alex L. KolodkinAbstract:Neuropilins bind secreted members of the semaphorin family of proteins. Neuropilin-1 is a receptor for Sema III. Here, we show that Neuropilin-2 is a receptor for the secreted semaphorin Sema IV and acts selectively to mediate repulsive guidance events in discrete populations of neurons. Neuropilin-2 and semaIV are expressed in strikingly complementary patterns during neurodevelopment. The extracellular complement-binding (CUB) and coagulation factor domains of Neuropilin-2 confer specificity to the Sema IV repulsive response, and these domains of Neuropilin-1 are necessary and sufficient for binding of the Sema III semaphorin (sema) domain. The coagulation factor domains alone are necessary and sufficient for binding of the Sema III immunoglobulin- (Ig-) basic domain and the unrelated ligand, vascular endothelial growth factor (VEGF). Lastly, Neuropilin-1 can homomultimerize and form heteromultimers with Neuropilin-2. These results provide insight into how interactions between Neuropilins and secreted semaphorins function to coordinate repulsive axon guidance during neurodevelopment.
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Neuropilin is a semaphorin III receptor.
Cell, 1997Co-Authors: Alex L. Kolodkin, Roman J. Giger, Dorothy V. Levengood, Erica G. Rowe, Yu Tzu Tai, David D. GintyAbstract:The semaphorin family contains a large number of phylogenetically conserved proteins and includes several members that have been shown to function in repulsive axon guidance. Semaphorin III (Sema III) is a secreted protein that in vitro causes neuronal growth cone collapse and chemorepulsion of neurites, and in vivo is required for correct sensory afferent innervation and other aspects of development. The mechanism of Sema III function, however, is unknown. Here, we report that Neuropilin, a type I transmembrane protein implicated in aspects of neurodevelopment, is a Sema III receptor. We also describe the identification of Neuropilin-2, a related Neuropilin family member, and show that Neuropilin and Neuropilin-2 are expressed in overlapping, yet distinct, populations of neurons in the rat embryonic nervous system.
Joost Verhaagen - One of the best experts on this subject based on the ideXlab platform.
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cellular toxicity following application of adeno associated viral vector mediated rna interference in the nervous system
BMC Neuroscience, 2010Co-Authors: Erich M E Ehlert, Ruben Eggers, Simone P Niclou, Joost VerhaagenAbstract:Background After a spinal cord lesion, axon regeneration is inhibited by the presence of a diversity of inhibitory molecules in the lesion environment. At and around the lesion site myelin-associated inhibitors, chondroitin sulfate proteoglycans (CSPGs) and several axon guidance molecules, including all members of the secreted (class 3) Semaphorins, are expressed. Interfering with multiple inhibitory signals could potentially enhance the previously reported beneficial effects of blocking single molecules. RNA interference (RNAi) is a tool that can be used to simultaneously silence expression of multiple genes. In this study we aimed to employ adeno-associated virus (AAV) mediated expression of short hairpin RNAs (shRNAs) to target all Semaphorin class 3 signaling by knocking down its receptors, Neuropilin 1 (Npn-1) and Neuropilin 2 (Npn-2).
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semaphorin 3a displays a punctate distribution on the surface of neuronal cells and interacts with proteoglycans in the extracellular matrix
Molecular and Cellular Neuroscience, 2005Co-Authors: Joris De Wit, Fred De Winter, Jan Klooster, Joost VerhaagenAbstract:Secreted semaphorins are essential for neural development and continue to be expressed in subpopulations of adult neurons, where they subserve as yet unknown functions. We employed functional myc- and GFP-tagged Sema3A proteins to obtain insight in the localization of Sema3A in neuronal cells. Sema3A localized to both axons and dendrites of cortical neurons. GFP-Sema3A exhibited a characteristic punctate distribution on the surface of Neuro-2a cells, localized to migratory pathways of cultured cells, and co-localized with and induced clustering of its receptor component Neuropilin-1. Treatment with excess glycosaminoglycans and chondroitinase ABC resulted in the removal of cell surface Sema3A. Heparin enhanced Sema3A's binding to Neuropilin-1-expressing cells and potentiated its growth cone collapsing activity. Together, these results indicate that association with proteoglycans in the extracellular matrix of neuronal cells plays an important role in the localization of the chemorepulsive guidance cue Sema3A, and that this interaction may enhance its biological activity.
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expression of the gene encoding the chemorepellent semaphorin iii is induced in the fibroblast component of neural scar tissue formed following injuries of adult but not neonatal cns
Molecular and Cellular Neuroscience, 1999Co-Authors: R J Pasterkamp, Roman J. Giger, Marc J Ruitenberg, A J G D Holtmaat, F De Winter, Joost VerhaagenAbstract:This study evaluates the expression of the chemorepellent semaphorin III (D)/collapsin-1 (sema III) following lesions to the rat CNS. Scar tissue, formed after penetrating injuries to the lateral olfactory tract (LOT), cortex, perforant pathway, and spinal cord, contained numerous spindle-shaped cells expressing high levels of sema III mRNA. The properties of these cells were investigated in detail in the lesioned LOT. Most sema III mRNA-positive cells were located in the core of the scar and expressed proteins characteristic for fibroblast-like cells. Neuropilin-1, a sema III receptor, was expressed in injured neurons with projections to the lesion site, in a subpopulation of scar-associated cells and in blood vessels around the scar. In contrast to lesions made in the mature CNS, LOT transection in neonates did not induce sema III mRNA expression within cells in the lesion and was followed by vigorous axonal regeneration. The concomitant expression of sema III and its receptor Neuropilin-1 in the scar suggests that sema III/Neuropilin-1-mediated mechanisms are involved in CNS scar formation. The expression of the secreted chemorepellent sema III following CNS injury provides the first evidence that chemorepulsive semaphorins may contribute to the inhibitory effects exerted by scars on the outgrowth of injured CNS neurites. The vigorous regrowth of injured axons in the absence of sema III following early neonatal lesions is consistent with this notion. The inactivation of sema III in scar tissue by either antibody perturbation or by genetic or pharmacological intervention could be a powerful means to promote long-distance regeneration in the adult CNS.