Article abstract
Nature Neuroscience 11, 440 - 449 (2008)
Published online: 9 March 2008 | doi:10.1038/nn2064
Plexin-A2 and its ligand, Sema6A, control nucleus-centrosome coupling in migrating granule cells
Julie Renaud1,2, Géraldine Kerjan1,2, Itsuko Sumita3, Yvrick Zagar1,2, Virginie Georget2,4, Doyeun Kim5, Coralie Fouquet1,2, Kazunori Suda3, Makoto Sanbo6, Fumikazu Suto7, Susan L Ackerman5, Kevin J Mitchell8, Hajime Fujisawa3 & Alain Chédotal1,2,9,10
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.
- Centre National de la Recherche Scientifique, UMR7102, 9 Quai Saint-Bernard, Paris F-75005, France.
- Université Pierre et Marie Curie–Paris 6, UMR7102, Paris F-75005, France.
- Division of Biological Science, Nagoya University Graduate School of Science, Nagoya 468-8602, Japan.
- Institut Fédératif de Biologie Intégrative, 9 Quai Saint-Bernard, Paris F-75005, France.
- Howard Hughes Medical Institute, Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, USA.
- Laboratory of Neurobiology and Behavioral Genetics, National Institute for Physiological Science, Myodaiji, Okazaki 444-8585, Japan.
- Division of Developmental Genetics, National Institute of Genetics, Mishima 411-8540, Japan.
- Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland.
- AP-HP, Groupe Hospitalier Pitié-Salpétrière, Fédération de Neurologie, 91 Boulevard de l'Hôpital, Paris F-75013, France.
- Present address: Institut de la Vision, INSERM, UMR_S592, 17 rue Moreau, Paris F-75012, France.
Correspondence to: Alain Chédotal1,2,9,10 e-mail: chedotal@infobiogen.fr
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