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

Abstract

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.

Molecular and Functional Characterizations of Gastrula Organizer Cells Derived from Human Embryonic Stem Cells

“…These receptors are assumed to be involved, among other things, in the regulation of organizer localization and in directing cell migration during axis formation. Indeed, the receptors upregulated in GSC þ cells include, among others, PLXNA2 [44] and SEMA5A [45], known to take part in cellular position determination during axonal guidance. The genes upregulated in the GSC expressing cells may, therefore, posses a yet unknown role in the patterning of the mammalian and particularly the human axis.…”

Purinergic A2b Receptor Activation by Extracellular Cues Affects Positioning of the Centrosome and Nucleus and Causes Reduced Cell Migration

“…Par6␣ signaling controls centrosomal protein localization and cytoskeletal dynamics, which in turn coordinate centrosomal motion and neuronal migration (39). Uncoupling of the positioning of the centrosome and nucleus can severely perturb cell migration (8,79).…”

Translocation nucléaire dans les neurones en migration : rôle de la sémaphorine 6A et de son récepteur Plexine-A2

“…Nous avons tout d'abord montré que la plexine A2 est également exprimée par les cellules granulaires en migration tangentielle mais aussi par celles qui migrent de façon radiaire [8]. L'analyse du dévelop-pement du cervelet chez des souris déficientes pour la plexine A2 (une collaboration avec l'équipe du Dr Hajime Fujisawa, Université de Nagoya, Japon) a révélé des anomalies de migration des grains similaires à celles observées chez les souris déficientes en Séma6A.…”

“…De plus la polymérisation de l'actine est égale-ment anormale en l'absence de plexine-A2, entraînant l'apparition de nombreux filopodes à la surface des grains. De manière surprenante, l'absence de translocation du noyau dans les grains déficients en Séma6A semble être pour sa part corrélée à une absence de découplage entre noyau et centrosome [8]. Ces données mettent donc en évidence un nouveau rôle des molécules de guidage axonal, les séma-phorines, dans la migration neuronale, via une modulation du couplage noyaucentrosome.…”