GABAergic neurons regulate lateral ventricular development via transcription factor Pax5

Authors

  • Nobuhisa Ohtsuka,

    1. Program in Structural and Molecular Neuroscience, McLean Hospital, Belmont, Massachusetts
    2. Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
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    • N.O. and S.B. are primary authors with equal contributions.

  • Sylvia Badurek,

    1. Centre for Neuroregeneration, University of Edinburgh, Edinburgh, Scotland
    2. European Molecular Biology Laboratory, Monterotondo, Italy
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    • N.O. and S.B. are primary authors with equal contributions.

  • Meinrad Busslinger,

    1. Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria
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  • Francine M. Benes,

    1. Program in Structural and Molecular Neuroscience, McLean Hospital, Belmont, Massachusetts
    2. Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
    3. Program in Neuroscience, Harvard Medical School, Boston, Massachusetts
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    • F.M.B., L.M., and U.R. are senior authors with equal contributions.

  • Liliana Minichiello,

    1. Centre for Neuroregeneration, University of Edinburgh, Edinburgh, Scotland
    2. European Molecular Biology Laboratory, Monterotondo, Italy
    Current affiliation:
    1. Department of Pharmacology, University of Oxford, Oxford, UK
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    • F.M.B., L.M., and U.R. are senior authors with equal contributions.

  • Uwe Rudolph

    Corresponding author
    1. Program in Neuroscience, Harvard Medical School, Boston, Massachusetts
    2. Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, Massachusetts
    • Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
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    • F.M.B., L.M., and U.R. are senior authors with equal contributions.


  • The authors declare that there are no potential sources of conflict of interest.

  • This work was supported by NIMH MERIT AWARD R37 MH042261 Limbic lobe in Schizophrenia and Bipolar Disorder (Principal Investigator: F.M.B.), and an E-STAR fellowship funded by the EC's FP6 Marie Curie Host fellowship for Early Stage Research Training (MEST-CT-2004–504640) to S.B. M.B.'s research was supported by Boehringer Ingelheim.

Correspondence to: Uwe Rudolph, M.D. Laboratory of Genetic Neuropharmacology, McLean Hospital, Room MRC123A, 115 Mill Street, Belmont, MA 02478, USA, E-mail: urudolph@mclean.harvard.edu

Summary

Postmortem studies have revealed a downregulation of the transcription factor Pax5 in GABAergic neurons in bipolar disorder, a neurodevelopmental disorder, raising the question whether Pax5 in GABAergic neurons has a role in normal brain development. In a genetic approach to study functions of Pax5 in GABAergic neurons, Pax5 was specifically deleted in GABAergic neurons from Pax5 floxed mice using a novel Gad1-Cre transgenic mouse line expressing Cre recombinase in Gad1-positive, that is, GABAergic neurons. Surprisingly, these mice developed a marked enlargement of the lateral ventricles at approximately 7 weeks of age, which was lethal within 1–2 weeks of its appearance. This hydrocephalus phenotype was observed in mice homozygous or heterozygous for the Pax5 conditional knockout, with a gene dosage-dependent penetrance. By QTL (quantitative trait loci) mapping, a 3.5 Mb segment on mouse chromosome 4 flanked by markers D4Mit237 and D4Mit214 containing approximately 92 genes including Pax5 has previously been linked to differences in lateral ventricular size. Our findings are consistent with Pax5 being a relevant gene underlying this QTL phenotype and demonstrate that Pax5 in GABAergic neurons is essential for normal ventricular development. genesis 51:234–245. © 2013 Wiley Periodicals, Inc.

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