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The transmembrane semaphorin Sema6A controls cerebellar granule cell migration

Nature Neuroscience volume 8, pages 15161524 (2005) | Download Citation

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Abstract

The transmembrane semaphorin protein Sema6A is broadly expressed in the developing nervous system. Sema6A repels several classes of developing axons in vitro and contributes to thalamocortical axon guidance in vivo. Here we show that during cerebellum development, Sema6A is selectively expressed by postmitotic granule cells during their tangential migration in the deep external granule cell layer, but not during their radial migration. In Sema6A-deficient mice, many granule cells remain ectopic in the molecular layer where they differentiate and are contacted by mossy fibers. The analysis of ectopic granule cell morphology in Sema6a−/− mice, and of granule cell migration and neurite outgrowth in cerebellar explants, suggests that Sema6A controls the initiation of granule cell radial migration, probably through a modulation of nuclear and/or soma translocation. Finally, the analysis of mouse chimeras suggests that this function of Sema6A is primarily non-cell-autonomous.

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Change history

  • 09 October 2005

    Replaced supplementary figures 1-4.

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Acknowledgements

We thank C. Sotelo for his constant support and comments on the manuscript; H. Sakagami and H. Kondo (Tohoku University) for anti-β isoform of CaMKIV antibody; R. Hawkes (University of Calgary, Canada) for Zebrin II Q113 antibody; D. Karagogeos (University of Crete, Greece) for TAG-1 antibody; F. Qiu (UMDNJ, Piscataway, USA) for Barhl1 cDNA; M. Wassef (ENS, Paris, France) for Math1 cDNA; K. Skurka and D. Rottkamp for help in localizing the insertion site in the Sema6a gene trap allele; R. Schwartzmann and V. Georget (Service d'Imagerie IFR83, Université Paris 6, France) for their help with confocal and videomicroscopy studies; and M. Wassef, C. Lebrand, C. Métin and J.P. Baudoin for discussions. A.C. is supported by the Fondation pour la Recherche sur le Cerveau (FRC), the Schlumberger Foundation and the Association pour la Recherche sur le Cancer (ARC). K.J.M is a Science Foundation Ireland (SFI) Investigator. This work was supported by SFI grant 01/F.1/B006 to K.J.M; and grants from the 21st Century COE Program, and from the Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Agency (JST) to H.F.

Author information

Affiliations

  1. Centre National de la Recherche Scientifique UMR7102, Université de Paris 6, Case 12, 9 Quai Saint-Bernard, 75005 Paris, France.

    • Géraldine Kerjan
    •  & Alain Chédotal
  2. Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland.

    • Jackie Dolan
    •  & Kevin J Mitchell
  3. Centre National de la Recherche Scientifique UMR7622, Université de Paris 6, Batiment C, Case 24, 9 Quai Saint-Bernard, 75005 Paris, France.

    • Cécile Haumaitre
    •  & Sylvie Schneider-Maunoury
  4. The 21st Century Center of Excellence Program, Division of Biological Science, Nagoya University Graduate School of Science, Chikusa-ku, Nagoya 464–8602, Japan.

    • Hajime Fujisawa

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Alain Chédotal.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    BrdU pulse labelling.

  2. 2.

    Supplementary Fig. 2

    Distribution of granule cell precursors.

  3. 3.

    Supplementary Fig. 3

    Granule cell neurite outgrowth.

  4. 4.

    Supplementary Fig. 4

    Model of Sema6A function.

Videos

  1. 1.

    Supplementary Video 1

    Time-lapse video 1 of migrating wild-type neurons. Migration of wild-type granule cells from an EGL microexplant after 24 h in culture. The explant is on the left of the frame. Granule cells migrate away from the explant. They also extend long processes bearing dynamic growth cones.

  2. 2.

    Supplementary Video 2

    Time-lapse video 2 of migrating wild-type neurons. Wild-type EGL microexplant cultured for 24 h. The explant is on the top. The movement of the soma/nucleus is saltatory and preceded by the appearance of an elongated swelling just ahead of the nucleus.

  3. 3.

    Supplementary Video 3

    Time-lapse video 3 of migrating Sema6A−/− neurons. Sema6A−/− EGL microexplant after 24 h in culture. The explant is on the left of the frame. Many granule cells remains stationary, oscillating, and some move backward towards the explant. However the cells extend long neurites as active as wild-type ones.

  4. 4.

    Supplementary Video 4

    Time-lapse video 4 of migrating Sema6A−/− neurons. The explant is located on the left of the frame. The cell body of most Sema6A−/− granule cells does not move forward and one in the center of the frame move back toward the explant.

  5. 5.

    Supplementary Video 5

    Time-lapse video 5 of migrating Sema6A−/− neurons. The explant is on the left of the frame. Illustration of two migrating Sema6A−/− granule cells. One in the bottom moves rearward toward the explant, while the second one migrate in the correct direction.

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DOI

https://doi.org/10.1038/nn1555

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