Disease relevance of Nrp1

• We also describe that neuropilin-deprived dorsal root ganglion neurons are perfectly protected from growth cone collapse elicited by semaphorin III/D [1].
• These findings suggest that the neuropilin 1-mediated Sema3A signals regulate arrest and aggregation of sympathetic neuron precursors and sympathetic neurons themselves at defined target sites and axon fasciculation to produce the stereotyped sympathetic nerve pattern [2].
• Astrocytomas are an ideal system for furthering our understanding of the functional relevance, if any, of Npn-1 in tumor angiogenesis [3].
• Colocalization of neuropilin-1 and Flk-1 in retinal neovascularization in a mouse model of retinopathy [4].
• Hypoxia, the main physiological inducer of VEGF expression, decreased Npn-1 expression [3].
• Later, Nrp1/Sema3A signaling is essential for segmental dorsal root gangliogenesis and motor axonal fasciculation into ventral roots [5].

High impact information on Nrp1

• Loss of neuropilin function increases the number of interneurons that migrate into the striatum [6].
• This defect was not caused by isoform-specific differences in stimulating endothelial cell proliferation or by impaired isoform-specific signaling through the Nrp1 receptor [7].
• Sema3A, a prototypical semaphorin, acts as a chemorepellent or a chemoattractant for axons by activating a receptor complex comprising neuropilin-1 as the ligand-binding subunit and plexin-A1 as the signal-transducing subunit [8].
• Thus, Sema3A-Npn-1 and Sema3F-Npn-2 signaling control distinct steps of motor axon growth and guidance during the formation of spinal motor connections [9].
• The murine VEGF gene is alternatively transcribed to yield the VEGF(120), VEGF(164), and VEGF(188) isoforms, which differ in their potential to bind to heparan sulfate and neuropilin-1 and to stimulate endothelial growth [10].

Biological context of Nrp1

• Both anti-NP1 and anti-KDR peptides induced endothelial cell apoptosis [11].
• Differential expression of VEGF isoforms and VEGF(164)-specific receptor neuropilin-1 in the mouse uterus suggests a role for VEGF(164) in vascular permeability and angiogenesis during implantation [12].
• They also reveal that endocytosis controlled by L1/NP-1 cis and trans interactions is pivotal in Sema3A-mediated axon guidance [13].
• 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 [13].
• These results provide evidence that Sema3A inhibits branching morphogenesis in lung bud organ cultures via NP-1 as a receptor or a component of a possible multimeric Sema3A receptor complex [14].

Anatomical context of Nrp1

• Recent work has shown that neuropilin-1 is essential but not sufficient to form functional Sema3A receptors and indicates that additional components are required to transduce signals from the cell surface to the cytoskeleton [15].
• Neuropilin-1 extracellular domains mediate semaphorin D/III-induced growth cone collapse [16].
• Neuropilin-1 (Npn-1), a receptor for semaphorin III, mediates the guidance of growth cones on extending neurites [17].
• An alternate VEGFR, VEGFR-1 or neuropilin-1, may modulate adhesion of leukocytes to tumor vessels [18].
• In contrast, we observed high expression of NP-1 in vessels, neurons, and astrocytes surrounding the infarct [19].

Associations of Nrp1 with chemical compounds

• Binding studies and confocal microscopy indicate that the target for the HBDt.TFt seems to be a trimolecular complex of chondroitin C sulfate proteoglycan, neuropilin-1, and VEGF receptor-2, overexpressed together only in highly angiogenic sites of the tumor microenvironment [20].
• Neuropilin (previously A5) is a cell surface glycoprotein that was originally identified in Xenopus tadpole nervous tissues [21].
• The selected peptide, ATWLPPR, inhibited the VEGF(165) binding to NRP-1 but not to tyrosine kinase receptors, VEGFR-1 (flt-1) and KDR; nor did it bind to heparin [22].
• The multimers are composed of disulfide-linked dimers attached noncovalently by interactions involving the meprin, A5 protein, receptor protein-tyrosine phosphatase mu (MAM) domain [23].
• Treatment with actinomycin D totally abolished both constitutive CYP 2 A 5 expression and its inducibility, suggesting that a transcriptional component is involved [24].

Physical interactions of Nrp1

• Plexin/neuropilin complexes mediate repulsion by the axonal guidance signal semaphorin 3A [15].
• Somatosensory axon outgrowth is repulsed when soluble semaphorin D (semD) binds to growth cone neuropilin-1 (Npn-1) [16].
• 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 [13].
• Nrp-1 also binds the VEGF-A splice isoform VEGF165, stimulates angiogenesis, and is necessary for vascular development in the mouse [25].

Regulatory relationships of Nrp1

• Taken together, our findings suggest that Fes links Sema3A signals to CRMP-CRAM, and that NP-1 negatively regulates PlexA1 activation by Fes in resting condition [26].
• Collapsin-1 induces growth cone collapse via a pathway which may include neuropilin-1, a cellsurface collapsin-1 binding protein, as well as intracellular CRMP-62 and heterotrimeric G proteins [27].
• Taken together, our findings suggest that Nurr1 might influence the processes of axon guidance and/or angiogenesis via the regulation of Nrp1 expression [28].
• Targeted inactivation of the neuropilin-1 gene in mice induced disorganization of the pathway and projection of nerve fibers, suggesting that neuropilin-1 mediates semaphorin-elicited signals and regulates nerve fiber guidance in embryogenesis [29].
• Semaphorin 3A (Sema3A) repels growing olfactory axons that express neuropilin-1 (NP-1), a receptor for Sema3A [30].

Other interactions of Nrp1

• Crosslinking experiments showed that (125)I-VEGF(165) binds to both NRP1 and VEGFR2 present in decidual endothelial cells [12].
• These results suggest that NRPs are early genes in embryonic vessel development and that both NP1 and NP2 are required [31].
• Examination of the expression of angiogenic factors that were induced after each cycle of activation, demonstrated that Hif-1a, Nrp1, and VEGF-A were all cyclically induced after each increment of distraction [32].
• COS-7 cells coexpressing plexin-A4 with neuropilin-1 were induced to contract by Sema3A, a member of the class 3 semaphorin [33].
• 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 [34].

Analytical, diagnostic and therapeutic context of Nrp1

• Confocal microscopy using 5-(6)-carboxyfluorescein-labelled peptides showed that anti-NP1 bound to both tumour and endothelial cells, whereas anti-KDR bound endothelial cells only [11].
• Immunohistochemistry and in situ hybridization experiments revealed that NIP expression overlaps with that of Npn-1 [17].
• The physiological interaction of Npn-1 and NIP is supported by co-immunoprecipitation of these two proteins in extracts from a heterologous expression system and from a native tissue [17].
• The localization of NP-1 was also confirmed by immunohistochemistry [4].
• To examine whether semaphorins could modulate VEGF endothelial cell guidance cues in the developing kidney, we studied the expression of semaphorin 3A and semaphorin 3F and their receptors NP-1 and NP-2 in the kidney during ontogeny using Northern blot analysis, in situ hybridization, Western blot analysis and immunohistochemistry [35].

References