Cortical-layer-specific effects of PACAP and tPA on interneuron migration during post-natal development of the cerebellum

Authors

  • Emilie Raoult,

    1. Inserm, PRIMACEN, Cell Imaging Platform of Normandy, Mont-Saint-Aignan, France
    2. University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France
    3. Inserm, U982, DC2N, Mont-Saint-Aignan, France
    4. International Associated laboratory Samuel de Champlain, Inserm-INRS, France
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    • These authors contributed equally to this work.
  • Magalie Bénard,

    1. Inserm, PRIMACEN, Cell Imaging Platform of Normandy, Mont-Saint-Aignan, France
    2. University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France
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    • These authors contributed equally to this work.
  • Hitoshi Komuro,

    1. Department of Neuroscience/NC30, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
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  • Alexis Lebon,

    1. Inserm, PRIMACEN, Cell Imaging Platform of Normandy, Mont-Saint-Aignan, France
    2. University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France
    3. Inserm, U982, DC2N, Mont-Saint-Aignan, France
    4. International Associated laboratory Samuel de Champlain, Inserm-INRS, France
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  • Denis Vivien,

    1. Inserm, U919, SP2U, Cyceron, Caen, France
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  • Alain Fournier,

    1. International Associated laboratory Samuel de Champlain, Inserm-INRS, France
    2. Institut National de la Recherche Scientifique — Institut Armand-Frappier, Université du Québec, Laval, Canada
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  • Hubert Vaudry,

    1. Inserm, PRIMACEN, Cell Imaging Platform of Normandy, Mont-Saint-Aignan, France
    2. University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France
    3. Inserm, U982, DC2N, Mont-Saint-Aignan, France
    4. International Associated laboratory Samuel de Champlain, Inserm-INRS, France
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  • David Vaudry,

    1. Inserm, PRIMACEN, Cell Imaging Platform of Normandy, Mont-Saint-Aignan, France
    2. University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France
    3. Inserm, U982, DC2N, Mont-Saint-Aignan, France
    4. International Associated laboratory Samuel de Champlain, Inserm-INRS, France
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  • Ludovic Galas

    Corresponding author
    1. Inserm, PRIMACEN, Cell Imaging Platform of Normandy, Mont-Saint-Aignan, France
    2. University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France
    • Address correspondence and reprint requests to Ludovic Galas, Inserm, PRIMACEN, Cell Imaging Platform of Normandy, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, Place E. Blondel, 76821 Mont-Saint-Aignan, France. E-mail: ludovic.galas@univ-rouen.fr

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Abstract

During early post-natal development of the cerebellum, granule neurons (GN) execute a centripetal migration toward the internal granular layer, whereas basket and stellate cells (B/SC) migrate centrifugally to reach their final position in the molecular layer (ML). We have previously shown that pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates in vitro the expression and release of the serine protease tissue-type plasminogen activator (tPA) from GN, but the coordinated role of PACAP and tPA during interneuron migration has not yet been investigated. Here, we show that endogenous PACAP is responsible for the transient arrest phase of GN at the level of the Purkinje cell layer (PCL) but has no effect on B/SC. tPA is devoid of direct effect on GN motility in vitro, although it is widely distributed along interneuron migratory routes in the ML, PCL, and internal granular layer. Interestingly, plasminogen activator inhibitor 1 reduces the migration speed of GN in the ML and PCL, and that of B/SC in the ML. Taken together, these results reveal for the first time that tPA facilitates the migration of both GN and fast B/SC at the level of their intersection in the ML through degradation of the extracellular matrix.

image

Crucial role of tissue plasminogen activator (tPA) in interneuron migration. Interneuron migration is a critical step for normal establishment of neuronal network. This study indicates that, in the post-natal cerebellum, tPA facilitates the opposite migration of immature excitatory granule neurons (GN) and immature inhibitory basket/stellate cells (B/SC) along the same migratory route. These data show that tPA exerts a pivotal role in neurodevelopment.

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