Alternative titles; symbols
HGNC Approved Gene Symbol: NRP2
Cytogenetic location: 2q33.3 Genomic coordinates (GRCh38) : 2:205,682,501-205,798,131 (from NCBI)
The complex wiring of the adult nervous system depends on the occurrence during neurodevelopment of an ordered series of axon guidance decisions that ultimately lead to the establishment of precise connections between neurons and their appropriate targets. These guidance events can act over long or short distances, and they can be either attractive or repulsive in nature (Tessier-Lavigne and Goodman, 1996). The semaphorin family contains a large number of phylogenetically conserved proteins and includes several members that function in repulsive axon guidance. Semaphorin III (SEMA3A; 603961) 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. Kolodkin et al. (1997) reported that neuropilin-1 (NRP1; 602069), a type I transmembrane protein implicated in aspects of neurodevelopment, is a semaphorin III receptor. They also identified rat neuropilin-2, a related neuropilin family member, and showed that neuropilin and neuropilin-2 are expressed in overlapping, yet distinct, populations of neurons in the rat embryonic nervous system.
By RT-PCR of a prostate cell line cDNA library, Rossignol et al. (2000) cloned several splice variants of the NRP2 gene. The longest deduced protein contains 926 amino acids and shares domain characteristics with NRP1, including 2 N-terminal tandem CUB domains, followed by 2 coagulation factor domains, a MAM homology domain, a transmembrane domain, and a C-terminal cytoplasmic domain. The various membrane-associated isoforms fall into 2 main groups, designated NRP2a and NRP2b, that differ predominantly in their C termini. Northern blot analysis detected NRP2a transcripts in heart, small intestine, placenta, liver, and lung. NRP2b transcripts were detected in heart, small intestine, and skeletal muscle. Rossignol et al. (2000) also identified a 555-amino acid soluble NRP2 protein that has a truncation within the second coagulation factor domain. The soluble NRP2 was secreted as a 62.5-kD protein following transfection in Chinese hamster ovary cells.
Most striatal and cortical interneurons arise from the basal telencephalon, later segregating to their respective targets. Marin et al. (2001) demonstrated that migrating cortical interneurons avoid entering the striatum because of a chemorepulsive signal composed at least in part of semaphorin-3A and semaphorin-3F (601124). 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. Marin et al. (2001) concluded that their 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.
Gong et al. (2003) described a large-scale screen to create an atlas of CNS gene expression at the cellular level, and to provide a library of verified bacterial artificial chromosome (BAC) vectors and transgenic mouse lines that offer experimental access to CNS regions, cell classes, and pathways. They demonstrated that Sema3b (601281) is involved in axon-target interactions. Sema3b can act to repulse axons expressing neuropilin-2 and can antagonize the repulsive action of Sema3a on axonal growth cones expressing neuropilin-1.
Tran et al. (2009) demonstrated that a secreted semaphorin, Sema3F, is a negative regulator of spine development and synaptic structure. Mice with null mutations in genes encoding Sema3F, and its holoreceptor components Npn2 and plexin A3 (PLEXA3; 300022), exhibit increased dentate gyrus granule cell and cortical layer V pyramidal neuron spine number and size, and also aberrant spine distribution. Moreover, Sema3F promotes loss of spines and excitatory synapses in dissociated neurons in vitro, and in Npn2-null brain slices cortical layer V and dentate gyrus granule cells exhibit increased miniature excitatory postsynaptic current frequency. In contrast, a distinct Sema3A (603961)-Npn1 (602069)/PlexA4 (604280) signaling cascade controls basal dendritic arborization in layer V cortical neurons, but does not influence spine morphogenesis or distribution. These disparate effects of secreted semaphorins are reflected in the restricted dendritic localization of Npn2 to apical dendrites and of Npn1 to all dendrites of cortical pyramidal neurons. Therefore, Sema3F signaling controls spine distribution along select dendritic processes, and distinct secreted semaphorin signaling events orchestrate CNS connectivity through the differential control of spine morphogenesis, synapse formation, and elaboration of dendritic morphology.
Using microarray analysis, Dutta et al. (2016) found that human WDFY1 (618080) was specifically regulated by NRP2. Depletion of NRP2 in PC3 prostate cancer cells increased both the mRNA and protein levels of WDFY1. Stability assays indicated that NRP2 did not regulate WDFY1 expression by altering its mRNA or protein stability. Instead, enhanced expression of WDFY1 following depletion of NRP2 was due to increased WDFY1 transcriptional activity, as shown in promoter activity assays. Analysis of the WDFY1 promoter region identified FAC1 (601819) as a transcriptional repressor whose binding to the promoter was regulated by NRP2, as confirmed in a chromatin immunoprecipitation assay and knockdown studies. In the presence of NPR2, FAC1 bound to the WDFY1 promoter region and downregulated WDFY1 transcriptional activity. Following NRP2 depletion, FAC1 was removed from the WDFY1 promoter and relocated from the nucleus to the cytosol, thereby releasing inhibition of WDFY1 transcription.
Martinez-Martin et al. (2018) identified NRP2 as a host receptor for human cytomegalovirus (HCMV) pentamer. Investigation of the expression of receptor NRP2 showed that the protein is expressed in ARPE-19 epithelial cells, endothelial cells (HUVECs), and MRC-9 fibroblasts, and increases susceptibility of the cells to HCMV infection. NRP2 is the functional receptor for the HCMV pentamer for infection of epithelial and endothelial cells. Expression of NRP2 with PDGFR-alpha (173490), the functional receptor of the HCMV trimer, results in the susceptibility of fibroblasts to HCMV trimer. The extracellular region of NRP2 contains 2 N-terminal CUB domains (a1 and a2), followed by 2 middle coagulation factor V/VIII homology domains (b1 and b2) and 1 C-terminal MAM domain, which is separated from the a1-a2-b1-b2 domains by a long flexible linker. Using a combination of biochemistry, cell-based assays, and electron microscopy to analyze the HCMV pentamer-NRP2 complex in epithelial/endothelial cells, Martinez-Martin et al. (2018) found that the a1 domain could undergo large conformational changes with respect to the remainder of NRP2 and interact with distinct region of the pentamer. Binding studies indicated that pentamer-specific neutralizing antibodies were able to block HCMV infection by preventing the binding between virus pentamer and NRP2 at the cell surface.
Rossignol et al. (2000) determined that the NRP2 gene contains 17 exons and spans about 112 kb. The NRP2b transcripts utilize a unique exon within intron 15, which the authors called exon 16b.
By somatic cell hybrid analysis, Rossignol et al. (1999) mapped the NRP2 gene to chromosome 2. They localized the NRP2 gene to 2q34 using radiation hybrid mapping.
Giger et al. (2000) generated mice with a targeted deletion in the neuropilin-2 (Npn2) gene. Many Npn2 mutant mice were viable into adulthood, thus allowing the authors to assess the role of Npn2 in axon guidance events throughout neural development. Npn2 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 were either severely disorganized or missing. Giger et al. (2000) concluded that Npn2 is a selective receptor for class 3 semaphorins in vivo and that Npn1 and Npn2 are required for development of an overlapping but distinct set of central nervous system and peripheral nervous system projections.
Chen et al. (2000) generated Nrp2-deficient mice using a gene trap strategy with the 'secretory trap vector.' The Nrp2 mutant mice were viable and fertile. Repulsive responses of sympathetic and hippocampal neurons to Sema3f but not to Sema3a were abolished in the mutant. The authors observed marked defects 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 mossy fiber axons in the infrapyramidal bundle. Chen et al. (2000) concluded that Nrp2 is an essential component of the Sema3f receptor. They identified key roles for Nrp2 in axon guidance in the peripheral and central nervous systems.
Takashima et al. (2002) showed that transgenic mice died in utero at embryonic day 8.5 when both Nrp1 and Nrp2, which they called Np1 and Np2, respectively, were knocked out. The yolk sacs of these mice were totally avascular. Mice deficient for Nrp2 but heterozygous for Nrp1 or deficient for Nrp1 but heterozygous for Nrp2 were also embryonic lethal and survived to embryonic days 10 to 10.5. Other details of the abnormal vascular phenotype resembled those of Vegf (192240) and Vefgr2 (191306) knockouts. The results suggested that neuropilins are early genes in embryonic vessel development and that both NRP1 and NRP2 are required.
Chen, H., Bagri, A., Zupicich, J. A., Zou, Y., Stoeckli, E., Pleasure, S. J., Lowenstein, D. H., Skarnes, W. C., Chedotal, A., Tessier-Lavigne, M. Neuropilin-2 regulates the development of select cranial and sensory nerves and hippocampal mossy fiber projections. Neuron 25: 43-56, 2000. [PubMed: 10707971] [Full Text: https://doi.org/10.1016/s0896-6273(00)80870-3]
Dutta, S., Roy, S., Polavaram, N. S., Baretton, G. B., Muders, M. H., Batra, S., Datta, K. NRP2 transcriptionally regulates its downstream effector WDFY1. Sci. Rep. 6: 23588, 2016. Note: Electronic Article. [PubMed: 27026195] [Full Text: https://doi.org/10.1038/srep23588]
Giger, R. J., Cloutier, J.-F., Sahay, A., Prinjha, R. K., Levengood, D. V., Moore, S. E., Pickering, S., Simmons, D., Rastan, S., Walsh, F. S., Kolodkin, A. L., Ginty, D. D., Geppert, M. Neuropilin-2 is required in vivo for selective axon guidance responses to secreted semaphorins. Neuron 25: 29-41, 2000. [PubMed: 10707970] [Full Text: https://doi.org/10.1016/s0896-6273(00)80869-7]
Gong, S., Zheng, C., Doughty, M. L., Losos, K., Didkovsky, N., Schambra, U. B., Nowak, N. J., Joyner, A., Leblanc, G., Hatten, M. E., Heintz, N. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425: 917-925, 2003. [PubMed: 14586460] [Full Text: https://doi.org/10.1038/nature02033]
Kolodkin, A. L., Levengood, D. V., Rowe, E. G., Tai, Y.-T., Giger, R. J., Ginty, D. D. Neuropilin is a semaphorin III receptor. Cell 90: 753-762, 1997. [PubMed: 9288754] [Full Text: https://doi.org/10.1016/s0092-8674(00)80535-8]
Marin, O., Yaron, A., Bagri, A., Tessier-Lavigne, M., Rubenstein, J. L. R. Sorting of striatal and cortical interneurons regulated by semaphorin-neuropilin interactions. Science 293: 872-875, 2001. [PubMed: 11486090] [Full Text: https://doi.org/10.1126/science.1061891]
Martinez-Martin, N., Marcandalli, J., Huang, C. S., Arthur, C. P., Perotti, M., Foglierini, M., Ho, H., Dosey, A. M., Shriver, S., Payandeh, J., Leitner, A., Lanzavecchia, A., Perez, L., Ciferri, C. A unbiased screen for human cytomegalovirus identifies neuropilin-2 as a central viral receptor. Cell 174: 1158-1171, 2018. [PubMed: 30057110] [Full Text: https://doi.org/10.1016/j.cell.2018.06.028]
Rossignol, M., Beggs, A. H., Pierce, E. A., Klagsbrun, M. Human neuropilin-1 and neuropilin-2 map to 10p12 and 2q34, respectively. Genomics 57: 459-460, 1999. [PubMed: 10329017] [Full Text: https://doi.org/10.1006/geno.1999.5790]
Rossignol, M., Gagnon, M. L., Klagsbrun, M. Genomic organization of human neuropilin-1 and neuropilin-2 genes: identification and distribution of splice variants and soluble isoforms. Genomics 70: 211-222, 2000. [PubMed: 11112349] [Full Text: https://doi.org/10.1006/geno.2000.6381]
Takashima, S., Kitakaze, M., Asakura, M., Asanuma, H., Sanada, S., Tashiro, F., Niwa, H., Miyazaki, J., Hirota, S., Kitamura, Y., Kitsukawa, T., Fujisawa, H., Klagsbrun, M., Hori, M. Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis. Proc. Nat. Acad. Sci. 99: 3657-3662, 2002. [PubMed: 11891274] [Full Text: https://doi.org/10.1073/pnas.022017899]
Tessier-Lavigne, M., Goodman, C. S. The molecular biology of axon guidance. Science 274: 1123-1133, 1996. [PubMed: 8895455] [Full Text: https://doi.org/10.1126/science.274.5290.1123]
Tran, T. S., Rubio, M. E., Clem, R. L., Johnson, D., Case, L., Tessier-Lavigne, M., Huganir, R. L., Ginty, D. D., Kolodkin, A. L. Secreted semaphorins control spine distribution and morphogenesis in the postnatal CNS. Nature 462: 1065-1069, 2009. [PubMed: 20010807] [Full Text: https://doi.org/10.1038/nature08628]