Abstract
BackgroundPlexins, known to date as receptors of semaphorins, are implicated in semaphorin-mediated axon repulsion and growth cone collapse. However, subtype-specific functions of the majority of the nine members of the mammalian plexin family are largely unknown. In order to investigate functional properties of B-plexins, we analyzed the expression of human and murine plexin B3 and expressed full-length human plexins B2 (B2) and B3 (B3) in NIH-3T3 cells.ResultsUnexpectedly, B3 strongly and B2 moderately stimulate neurite outgrowth of primary murine cerebellar neurons. Both plexins mediate Ca2+/Mg2+-dependent cell aggregation due to homophilic trans-interaction, which is strong in the case of B3 and moderate for B2. Using different deletion constructs we show that the sema domain of B3 is essential for homophilic interaction. Using yeast two-hybrid analysis, we identified the neuron-specific and calmodulin-binding Ras-related GTPase Rin as an interaction partner of the intracellular part of B3, but not of B2. Rin, also known for its neurite outgrowth-inducing characteristics, co-localizes and co-immunoprecipitates with B3 in co-transfected COS-7 cells.ConclusionOur data suggest an involvement of homophilic interaction of B3 in semaphorin-independent signaling mechanisms positively influencing neuronal morphogenesis or function. Furthermore the neuron-specific small GTPase Rin is involved in downstream signaling of plexin B3.
Highlights
Plexins, known to date as receptors of semaphorins, are implicated in semaphorinmediated axon repulsion and growth cone collapse
The nine mammalian plexins, A1–4, B1–3, C1, and D1 [3,4] are characterized by a sema domain, three cysteine-rich repeats (MRS, Metrelated sequences, or PSI, plexins, semaphorins, and integrins), three glycine/proline-rich repeats (IPT, immunoglobulin-like fold shared by plexins and transcription factors), a single-pass transmembrane region, and an intracellular SP domain consisting of two different parts [5]
Using a neurite outgrowth assay with murine cerebellar neurons and substrate cells expressing recombinant human plexins B2-expressing substrate cells (B2) or B3, we found evidence of neurite outgrowth-promoting activity of both plexins
Summary
Known to date as receptors of semaphorins, are implicated in semaphorinmediated axon repulsion and growth cone collapse. Semaphorin 5A induces growth cone collapse in retinal ganglion cells, has axon-repelling activity [18], induces cellular collapse, and leads to inhibition of integrin-based adhesion of NIH-3T3 fibroblasts expressing recombinant plexin B3 [17]. The cytoplasmic C-terminus of B plexins activates Rho GTPase through Rho guanine nucleotide exchange factors PDZ-RhoGEF and LARG [19,20,21,22,23,24]. Based on this C-terminal interaction, plexin B1 mediates semaphorin 4D-induced growth cone collapse in neurons [20]. According to published data, plexins appear to be mainly involved in the repulsive activities of semaphorins on neuronal cells
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