Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0344329 (collapse)
 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the initial stages of development, the notochord provides repulsive signals for dorsal root ganglion (DRG) axons via semaphorin 3A/neuropilin-1, axonin-1/SC2, and other unknown repulsive molecules. The notochord is known to produce aggrecan, one of the chondroitin sulfate proteoglycans (CSPGs). We report here that adding aggrecan to the culture medium cannot only induce DRG growth cone collapse, but also inhibit DRG axonal growth. Using cocultures composed of tissues derived from chick embryos or neuropilin-1-deficient mice treated with chondroitinase ABC, we show the direct evidence that CSPGs are involved in notochord-derived repulsion for DRG axons. At later developmental stages, CSPGs are involved in perinotochordal sheath-derived axon repulsion, but not in notochord core-derived repulsion. We further demonstrate that TAG-1/axonin-1/SC2 is not involved in mediating repulsive activities by CSPGs, but is required for notochord core-derived axon repulsion. Thus, notochord-derived multiple axon repulsions act in a spatiotemporal-specific manner to shape the initial trajectories of DRG axons.
 ...
PMID:Developmental regulation of notochord-derived repulsion for dorsal root ganglion axons. 1501 39

During axon navigation, Semaphorin3A-induced growth cone retraction is correlated with endocytosis. Although its function remains elusive, we showed previously that the cell adhesion molecule of the immunoglobulin super family L1 associates with Neuropilin-1 (NP-1) the Sema3A-binding subunit of the receptor complex and is required for Sema3A to elicit axonal repulsive responses. We report here that upon Sema3A binding to NP-1, L1 and NP-1 are co-internalized through a clathrin-dependent mechanism mediated by L1. We show that in COS7 cells, L1/NP-1 endocytosis is correlated with a cell contraction similar to that observed with the Plexin (Plex)/NP-1 or Plex/NP1/L1 complexes. In neuronal cultures, a L1-mimetic peptide able to switch Sema3A repulsive responses to attraction blocks both endocytosis and growth cone collapse. Similarly, in the COS7 cell model, peptide application prevents both the Sema3-induced L1/NP-1 internalization and cell collapse. These studies demonstrate that the L1/NP-1 complex is able to confer a biological response to Sema3A with L1 mediating receptor internalization following ligand activation. They also reveal that endocytosis controlled by L1/NP-1 cis and trans interactions is pivotal in Sema3A-mediated axon guidance.
 ...
PMID:Semaphorin3A-induced receptor endocytosis during axon guidance responses is mediated by L1 CAM. 1512 Nov 81

Vascular endothelial growth factor (VEGF) displays neurotrophic and neuroprotective activities, but the mechanisms underlying these effects have not been defined. Neuropilin-1 (NP-1) is a receptor for VEGF165 and placental growth factor-2 (PlGF-2), but the role of NP-1 in VEGF-dependent neurotrophic actions is unclear. Dorsal root ganglion (DRG) neurons expressed high levels of NP-1 mRNA and protein, much lower levels of KDR, and no detectable Flt-1. VEGF165 and PlGF-2 promoted DRG growth cone formation with an effect similar to that of nerve growth factor, whereas the Flt-1-specific ligand, PlGF-1, and the KDR/Flt-4 ligand, VEGF-D, had no effect. The chemorepellent NP-1 ligand, semaphorin 3A, antagonized the response to VEGF and PlGF-2. The specific KDR inhibitor, SU5614, did not affect the anti-chemorepellent effects of VEGF and PlGF-2, whereas a novel, specific antagonist of VEGF binding to NP-1, called EG3287, prevented inhibition of growth cone collapse. VEGF stimulated prostacyclin and prostaglandin E2 production in DRG cultures that was blocked by inhibitors of cyclooxygenases; the anti-chemorepellent activities of VEGF and PlGF-2 were abrogated by cyclooxygenase inhibitors, and a variety of prostacyclin analogues and prostaglandins strikingly inhibited growth cone collapse. These findings support a specific role for NP-1 in mediating neurotrophic actions of VEGF family members and also identify a novel role for prostanoids in the inhibition of neuronal chemorepulsion.
 ...
PMID:Anti-chemorepulsive effects of vascular endothelial growth factor and placental growth factor-2 in dorsal root ganglion neurons are mediated via neuropilin-1 and cyclooxygenase-derived prostanoid production. 1512 2

The chick embryo is widely used for the study of vertebrate development, but a general, reliable loss-of-function strategy for the analysis of gene function is currently not available. By using small inhibitory hairpin RNA (siRNA) molecules generated by the mouse U6 promoter, we have applied an RNA interference approach to achieve quantitative knockdown of the neuropilin-1 (Nrp-1) receptor in chick embryos. Functional knockdown was evident in the abolition of Sema3A-induced growth cone collapse in Nrp-1-siRNA but not Nrp-2-siRNA-expressing dorsal root ganglion (DRG) neurons. Two nervous system defects in Nrp-1 mutant mice were phenocopied in embryos treated with Nrp-1 siRNA. First, DRG axons prematurely entered the dorsal horn and projected inappropriately. Second, targeted early migrating neural crest cells destined for the sympathetic chain arrested ectopically within ventral spinal nerve roots. Localized knockdown induced by specific siRNA constructs will allow rapid functional analysis of genes regulating chick neural development whilst circumventing embryonic lethal effects often associated with global gene knockout in the mouse.
 ...
PMID:Functional knockdown of neuropilin-1 in the developing chick nervous system by siRNA hairpins phenocopies genetic ablation in the mouse. 1516 8

A secreted semaphorin, Sema3A, is an axon guidance molecule that induces collapse of growth cones and repels axons in vitro. Neuropilin-1 (Nrp-1) is a receptor for Sema3A. To clarify the function of the semaphorin in vivo, we generated Sema3A mutant mice and Nrp-1 mutant mice by targeted disruption of the Sema3A and Nrp-1 genes, respectively. These mutant mouse embryos showed a severe defect in the trajectory and projection of PNS efferent, suggesting that the Nrp-1-mediated Sema3A signals play crucial roles in the directional guidance of nerve fibers and the establishment of PNS networks. The deprivation of Nrp-1-mediated Sema3A signals also induced disorganization of the sympathetic nervous system. In the Nrp-1 and Sema3A mutant mouse embryos, more than half of the TH-positive SG neurons were distributed at ectopic positions. As a whole, the sympathetic trunk was severely disorganized. Sema3 A recombinant proteins inhibited migration of the wild-type (Nrp-1-expressing) but not Nrp-1-deficient SG neurons in culture, suggesting that Nrp-1-mediated Sema3A inhibitory signals are essential in precise migration of SG neurons, as well as directional guidance of axons.
 ...
PMID:[Roles of semaphorins in neuron network formation]. 1548 18

Because data from the literature suggest a lack of innervation of the placenta, we have investigated placenta, umbilical cord, and uterus to identify the molecules that play a role in regulating innervation in these organs. Neuropilin-1 and Plexin-A1 are cell surface proteins that form a receptor complex for Semaphorin 3A (Sema 3A), a secreted molecule mediating repelling signals for axonal growth cones. We have analyzed the expression of Neuropilin-1, Plexin-A1, and Semaphorin 3A in the above-mentioned tissues on the hypothesis that these molecules could regulate innervation in these organs during gestation. We found that nervous fibers are only present in the proximal part of the umbilical cord, close to the newborn, and in nongestational uterine tissues. In contrast, nervous fibers are not present in the distal segment of the umbilical cord, in the placenta and in the uterine tissues during gestation. We also found that Sema 3A receptors, Neuropilin-1 and Plexin-A1, are expressed by the nervous fibers of the proximal part of the umbilical cord, whereas Sema 3A is secreted in the umbilical cord, in the placenta, and in gestational uterine tissues. We report that a factor secreted in the umbilical cord induces the collapse of neurite growth cones in vitro and provide evidence that this factor is Sema 3A. In summary, our results suggest that the chemorepulsive signals mediated by Sema 3A play an important role in preventing nerve fibers growth in the umbilical cord and in gestational uterine tissues. The inhibition of nerve growth into the myometrium as well as into the placenta could be considered fundamental processes to preserve the fetus from external stressful events.
 ...
PMID:Restricted innervation of uterus and placenta during pregnancy: evidence for a role of the repelling signal Semaphorin 3A. 1551 71

Semaphorin 3A can inhibit axonal growth and induce neuronal apoptosis following binding to neuropilin-1, with the membrane proximal MAM (meprin, A5, mu) domain in neuropilin-1 playing a key role in the formation of a higher order receptor complex. If functional motifs on semaphorin 3A and/or the MAM domain can be identified, then small-constrained peptides might be developed as antagonists. We have scored peptide pairs for complementary hydropathy and antisense homology to identify a candidate functional motif in the Ig domain of semaphorin 3A, and in the MAM domain of neuropilin-1. Synthetic peptides corresponding to these sequences fully inhibit growth cone collapse induced by semaphorin 3A. A number of smaller peptides derived from the parental sequence also inhibited the response, particularly after they were constrained by a disulfide bond. Finally, we have used an algorithm to design a peptide that is a near-perfect hydropathic complement of the candidate functional site in the MAM domain; this also inhibits the semaphorin 3A response. Thus, an algorithm-driven methodology has led to the identification of three independent semaphorin 3A antagonists. Semaphorin 3F stimulates growth cone collapse following binding to the closest relative to neuropilin-1 in the genome, neuropilin-2. Where tested, the peptides that antagonise semaphorin 3A failed to inhibit the semaphorin 3F response.
 ...
PMID:A complementary peptide approach applied to the design of novel semaphorin/neuropilin antagonists. 1571 68

It has been proposed that four members of the plexin A subfamily (plexin-As; plexin-A1, -A2, -A3, and -A4) and two neuropilins (neuropilin-1 and neuropilin-2) form complexes and serve as receptors for class 3 secreted semaphorins (Semas), potent neural chemorepellents. The roles of given plexin-As in semaphorin signaling and axon guidance, however, are mostly unknown. Here, to elucidate functions of plexin-A4 in semaphorin signaling and axon guidance events in vivo, we generated plexin-A4 null mutant mice by targeted disruption of the plexin-A4 gene. Plexin-A4 mutant mice were defective in the trajectory and projection of peripheral sensory axons and sympathetic ganglion (SG) axons and the formation of the anterior commissure and the barrels. The defects in peripheral sensory and SG axons were fundamentally related to those of neuropilin-1 or Sema3A mutant embryos reported but were more moderate than the phenotype in these mutants. The growth cone collapse assay showed that dorsal root ganglion axons and SG axons of plexin-A4 mutant embryos partially lost their responsiveness to Sema3A. These results suggest that plexin-A4 plays roles in the propagation of Sema3A activities and regulation of axon guidance and that other members of the plexin-A subfamily are also involved in the propagation of Sema3A activities. Plexin-A4-deficient SG axons did not lose their responsiveness to Sema3F, suggesting that plexin-A4 serves as a Sema3A-specific receptor, at least in SG axons. In addition, the present study showed that plexin-A4 bound class 6 transmembrane semaphorins, Sema6A and Sema6B, and mediated their axon-repulsive activities, independently of neuropilin-1. Our results imply that plexin-A4 mediates multiple semaphorin signals and regulates axon guidance in vivo.
 ...
PMID:Plexin-a4 mediates axon-repulsive activities of both secreted and transmembrane semaphorins and plays roles in nerve fiber guidance. 1581 94

Semaphorins are a family of growth cone guidance molecules. When associated with their receptors and coreceptors, plexins and neuropilins, they act as chemorepellents for an extensive range of neuronal populations. The prototypic semaphorin, Sema3A, has a potent inhibitory effect on sensory axons emanating from dorsal root ganglia. This has formed the basis of the most famous assay for semaphorin activity, the chick dorsal root ganglia collapse assay. Recently, a heterologous, highly tractable assay has been used to investigate semaphorin signaling. In this system, the binding of recombinant semaphorins to COS cells expressing plexins and neuropilins induces a morphological collapse that may correlate with growth cone collapse. This chapter describes the optimization of this assay and outlines the subtle differences required to enable Sema3A-Fc and Sema4D-Fc to induce identical collapse phenotypes in COS cells expressing Plexin-A1 and neuropilin-1, or Plexin-B1, respectively.
 ...
PMID:Plexin-induced collapse assay in COS cells. 1647 96

The neural crest provides an excellent model system to study invasive cell migration, however it is still unclear how molecular mechanisms direct cells to precise targets in a programmed manner. We investigate the role of a potential guidance factor, neuropilin-1, and use functional knockdown assays, tissue transplantation and in vivo confocal time-lapse imaging to analyze changes in chick cranial neural crest cell migratory patterns. When neuropilin-1 function is knocked down in ovo, neural crest cells fail to fully invade the branchial arches, especially the 2nd branchial arch. Time-lapse imaging shows that neuropilin-1 siRNA transfected neural crest cells stop and collapse filopodia at the 2nd branchial arch entrances, but do not die. This phenotype is cell autonomous. To test the influence of population pressure and local environmental cues in driving neural crest cells to the branchial arches, we isochronically transplanted small subpopulations of DiI-labeled neural crest cells into host embryos ablated of neighboring, premigratory neural crest cells. Time-lapse confocal analysis reveals that the transplanted cells migrate in narrow, directed streams. Interestingly, with the reduction of neuropilin-1 function, neural crest cells still form segmental migratory streams, suggesting that initial neural crest cell migration and invasion of the branchial arches are separable processes.
 ...
PMID:In vivo analysis reveals a critical role for neuropilin-1 in cranial neural crest cell migration in chick. 1695 34


<< Previous 1 2 3 4 5 Next >>