The Neuropeptide Pituitary Adenylate Cyclase-Activating Polypeptide Exerts Anti-Apoptotic and Differentiating Effects during Neurogenesis: Focus on Cerebellar Granule Neurones and Embryonic Stem Cells

Authors

  • A. Falluel-Morel,

    1. INSERM U413, Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (IFRMP 23), University of Rouen, Mont-Saint-Aignan, France and Laboratoire International Associé Samuel de Champlain.
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  • M. Chafai,

    1. INSERM U413, Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (IFRMP 23), University of Rouen, Mont-Saint-Aignan, France and Laboratoire International Associé Samuel de Champlain.
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  • D. Vaudry,

    1. INSERM U413, Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (IFRMP 23), University of Rouen, Mont-Saint-Aignan, France and Laboratoire International Associé Samuel de Champlain.
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  • M. Basille,

    1. INSERM U413, Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (IFRMP 23), University of Rouen, Mont-Saint-Aignan, France and Laboratoire International Associé Samuel de Champlain.
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  • M. Cazillis,

    1. INSERM U676, Hôpital Robert Debré, Paris, France.
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  • N. Aubert,

    1. INSERM U413, Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (IFRMP 23), University of Rouen, Mont-Saint-Aignan, France and Laboratoire International Associé Samuel de Champlain.
    2. CIT, Evreux, France.
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  • E. Louiset,

    1. INSERM U413, Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (IFRMP 23), University of Rouen, Mont-Saint-Aignan, France and Laboratoire International Associé Samuel de Champlain.
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  • S. DeJouffrey,

    1. CIT, Evreux, France.
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  • J. F. Le Bigot,

    1. CIT, Evreux, France.
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  • A. Fournier,

    1. INRS − Institut Armand-Frappier, University of Québec, Pointe-Claire, Port de Québec, Canada.
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  • P. Gressens,

    1. INSERM U676, Hôpital Robert Debré, Paris, France.
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  • W. Rostène,

    1. INSERM U732, Hôpital Saint-Antoine, Paris, France.
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  • H. Vaudry,

    1. INSERM U413, Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (IFRMP 23), University of Rouen, Mont-Saint-Aignan, France and Laboratoire International Associé Samuel de Champlain.
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  • B. J. Gonzalez

    1. INSERM U413, Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (IFRMP 23), University of Rouen, Mont-Saint-Aignan, France and Laboratoire International Associé Samuel de Champlain.
    2. INSERM Avenir, School of Medicine and Pharmacy, University of Rouen, Rouen, France.
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Dr Hubert Vaudry and Dr Bruno Gonzalez, INSERM U413, Laboratory of Cellular and Molecular Neuroendocrinology, European Institute for Peptide Research (IFRMP 23), University of Rouen, 76821 Mont-Saint-Aignan, France (e-mails: hubert.vaudry@univ-rouen.fr and bruno.gonzales@univ-rouen.fr).

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) was originally isolated from ovine hypothalamus on the basis of its hypophysiotrophic activity. It has subsequently been shown that PACAP and its receptors are widely distributed in the central nervous system of adult mammals, indicating that PACAP may act as a neurotransmitter and/or neuromodulator. It has also been found that PACAP and its receptors are expressed in germinative neuroepithelia, suggesting that PACAP could be involved in neurogenesis. There is now compelling evidence that PACAP exerts neurotrophic activities in the developing cerebellum and in embryonic stem (ES) cells. In particular, the presence of PACAP receptors has been demonstrated in the granule layer of the immature cerebellar cortex, and PACAP has been shown to promote survival, inhibit migration and activate neurite outgrowth of granule cell precursors. In cerebellar neuroblasts, PACAP is a potent inhibitor of the mitochondrial apoptotic pathway through activation of the MAPkinase extracellular regulated kinase. ES cells and embryoid bodies (EB) also express PACAP receptors and PACAP facilitates neuronal orientation and induces the appearance of an electrophysiological activity. Taken together, the anti-apoptotic and pro-differentiating effects of PACAP characterised in cerebellar neuroblasts as well as ES and EB cells indicate that PACAP acts not only as a neurohormone and a neurotransmitter, but also as a growth factor.

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