CXCR4 prevents dispersion of granule neuron precursors in the adult dentate gyrus

Authors

  • Clara Schultheiß,

    1. Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
    Search for more papers by this author
  • Philipp Abe,

    1. Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
    Search for more papers by this author
  • Frauke Hoffmann,

    1. Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
    Search for more papers by this author
  • Wiebke Mueller,

    1. Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
    Search for more papers by this author
  • Anna-Elisabeth Kreuder,

    1. Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
    Search for more papers by this author
  • Dagmar Schütz,

    1. Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
    Search for more papers by this author
  • Sammy Haege,

    1. Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
    Search for more papers by this author
  • Christoph Redecker,

    1. Hans Berger Department of Neurology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
    Search for more papers by this author
  • Silke Keiner,

    1. Hans Berger Department of Neurology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
    Search for more papers by this author
  • Suresh Kannan,

    1. CRTD—Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
    2. DZNE, German Center for Neurodegenerative Diseases, Dresden, Germany
    Search for more papers by this author
  • Jan-Hendrik Claasen,

    1. CRTD—Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
    2. DZNE, German Center for Neurodegenerative Diseases, Dresden, Germany
    3. Department of Neurology, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
    Search for more papers by this author
  • Frank W. Pfrieger,

    1. Institute of Cellular and Integrative Neurosciences (INCI), CNRS UPR 3212, University of Strasbourg, Strasbourg, France
    Search for more papers by this author
  • Ralf Stumm

    Corresponding author
    1. Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Jena, Germany
    • Correspondence to: Ralf Stumm, Institut fuer Pharmakologie und Toxikologie, Drackendorfer Str. 1, 07747 Jena, Germany. E-mail: ralf.stumm@med.uni-jena.de

    Search for more papers by this author

  • C.S. and P.A. contributed equally to this work.

Abstract

Neurogenesis in the adult dentate gyrus (DG) generates new granule neurons that differentiate in the inner one-third of the granule cell layer (GCL). The migrating precursors of these neurons arise from neural stem cells (NSCs) in the subgranular zone (SGZ). Although it is established that pathological conditions, including epilepsy and stroke, cause dispersion of granule neuron precursors, little is known about the factors that regulate their normal placement. Based on the high expression of the chemokine CXCL12 in the adult GCL and its role in guiding neuronal migration in development, we addressed the function of the CXCL12 receptor CXCR4 in adult neurogenesis. Using transgenic reporter mice, we detected Cxcr4-GFP expression in NSCs, neuronal-committed progenitors, and immature neurons of adult and aged mice. Analyses of hippocampal NSC cultures and hippocampal tissue by immunoblot and immunohistochemistry provided evidence for CXCL12-promoted phosphorylation/activation of CXCR4 receptors in NSCs in vivo and in vitro. Cxcr4 deletion in NSCs of the postnatal or mature DG using Cre technology reduced neurogenesis. Fifty days after Cxcr4 ablation in the mature DG, the SGZ showed a severe reduction of Sox2-positive neural stem/early progenitor cells, NeuroD-positive neuronal-committed progenitors, and DCX-positive immature neurons. Many immature neurons were ectopically placed in the hilus and inner molecular layer, and some developed an aberrant dendritic morphology. Only few misplaced cells survived permanently as ectopic neurons. Thus, CXCR4 signaling maintains the NSC pool in the DG and specifies the inner one-third of the GCL as differentiation area for immature granule neurons. © 2013 Wiley Periodicals, Inc.

Ancillary