Plexin-A2 and its ligand, Sema6A, control nucleus-centrosome coupling in migrating granule cells.

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Renaud, Julie | Kerjan, Géraldine | Sumita, Itsuko | Zagar, Yvrick | Georget, Virginie | Kim, Doyeun | Fouquet, Coralie | Suda, Kazunori | Sanbo, Makoto | Suto, Fumikazu | Ackerman, Susan L | Mitchell, Kevin J | Fujisawa, Hajime | Chédotal, Alain

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During their migration, cerebellar granule cells switch from a tangential to a radial mode of migration. We have previously demonstrated that this involves the transmembrane semaphorin Sema6A. We show here that plexin-A2 is the receptor that controls Sema6A function in migrating granule cells. In plexin-A2-deficient (Plxna2(-/-)) mice, which were generated by homologous recombination, many granule cells remained in the molecular layer, as we saw in Sema6a mutants. A similar phenotype was observed in mutant mice that were generated by mutagenesis with N-ethyl-N-nitrosourea and had a single amino-acid substitution in the semaphorin domain of plexin-A2. We found that this mutation abolished the ability of Sema6A to bind to plexin-A2. Mouse chimera studies further suggested that plexin-A2 acts in a cell-autonomous manner. We also provide genetic evidence for a ligand-receptor relationship between Sema6A and plexin-A2 in this system. Using time-lapse video microscopy, we found that centrosome-nucleus coupling and coordinated motility were strongly perturbed in Sema6a(-/-) and Plxna2(-/-) granule cells. This suggests that semaphorin-plexin signaling modulates cell migration by controlling centrosome positioning.

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