HISTORICAL CONTEXT

Neuropilins (NRPs) are type I membrane glycoproteins first described by Fujisawa and colleagues in 1987 as antigens for antibodies that bind to neuropiles and plexiform layers in the Xenopus tadpole nervous system (1,2). NRP function was demonstrated 10 years later when these proteins were found to be receptors for the class 3 semaphorins (SEMA). The first class 3 semaphorin identified was chick collapsin-1 (now known as Sema3A), described by Raper and colleagues as an inhibitory axonal guidance signal that collapsed growth cones and repelled axons in chick dorsal root ganglia (DRG) (1–4). Two NRPs (NRP1 and NRP2), and six class 3 semaphorins (A-F) exist (5,6).

Unexpectedly, NRPs were later shown to be regulators of angiogenesis. The first indication came in 1995, when over-expression of Nrp1 in chimeric mice was associated with vascular defects (7). In 1998, NRP1 was detected in endothelial cells (ECs) for the first time (8). ECs express both NRP1 and NRP2, and these NRPs are functional receptors for vascular endothelial growth factor (VEGF), a potent angiogenesis factor (5). NRPs do not appear to be high-affinity receptor tyrosine kinases but may serve as coreceptors with high-affinity VEGF receptors. A complex of VEGF-A165, NRP1, and VEGF receptor 2 (VEGFR2) is formed on ECs that increases VEGF binding and enhances EC chemotaxis (8,9). ECs that express NRPs also bind semaphorins. Plexins (PLXNs), a large family of transmembrane proteins, form complexes with SEMAs and NRPs and function as signaling coreceptors (10). As an example of the effect of SEMA on ECs, SEMA3A inhibits EC migration and sprouting (11), and SEMA3 Finhibits tumor angiogenesis and metastasis (12). These findings are discussed in more detail in later sections.