Genomic organization of human neuropilin-1 and neuropilin-2 genes: Identification and distribution of splice variants and soluble isoforms

Neuropilin-1 (NRP1) and neuropiln-2 (NRP2) are both receptors for semaphori ns, which regulate neuronal guidance, and vascular endothelial growth facto r (VEGF), an angiogenic factor. The two human NRP1 and NRP2 genes were clon ed, and the exon-intron boundaries were determined. The NRP1 and NRP2 genes span over 120 and 112 kb, respectively, and are composed of 17 exons. Five of the exons are identical in size in the two genes, suggesting that they arose by gene duplication. Both NRP genes are characterized by multiple alt ernatively spliced variants. Two NRP2 isoforms, NRP2a and NRP2b, were clone d. A striking feature of these two isoforms is that they have identical ext racellular domains but have divergent transmembrane and cytoplasmic domains . In these domains, NRP2a is closer in sequence identity to NRP1 than to NR P2b. As determined by Northern blot analysis, both NRP2a and NRP2b are expr essed in a variety of tissues, mostly in a nonoverlapping manner. Within NR P2a and NRP2b, there are several alternatively spliced species: NRP2a(17), NRP2a(22), NRP2b(0), and NRP2b(5). In addition to full-length NRPs, there a re truncated NRPs as well, which contain only the extracellular a/CUB and b /coagulation factor domains. These genes encode proteins that are soluble ( sNRP) and released by cells. In addition to s(12)NRP1, which was previously cloned, s(11)NRP1 and s(9)NRP2 have now been cloned. These sNRP molecules are characterized by having intron-derived sequences at their C-termini. Al together, eight NRP isoforms are described in this report. It was concluded that there are multiple NRP1 and NRP2 isoforms including intact and solubl e forms. Characterization of these isoforms hsould help to elucidate the fu nction of NRPs in neuronal guidance and angiogenesis. (C) 2000 Academic Pre ss.