Distinct molecular pathways for development of telencephalic interneuron subtypes revealed through analysis of Lhx6 mutants

Authors

  • Yangu Zhao,

    1. Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, Maryland 20892
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    • The first three authors contributed equally to this work.

  • Pierre Flandin,

    1. Department of Psychiatry and the Nina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco, San Francisco, California 94158-2324
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    • The first three authors contributed equally to this work.

  • Jason E. Long,

    1. Department of Psychiatry and the Nina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco, San Francisco, California 94158-2324
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    • The first three authors contributed equally to this work.

  • Melissa Dela Cuesta,

    1. Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, Maryland 20892
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  • Heiner Westphal,

    1. Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, Bethesda, Maryland 20892
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  • John L.R. Rubenstein

    Corresponding author
    1. Department of Psychiatry and the Nina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco, San Francisco, California 94158-2324
    • Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, 2nd Floor South, Room GD 284C, UCSF, 1550 4th Street, San Francisco, CA 94143-2611
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Abstract

Here we analyze the role of the Lhx6 lim-homeobox transcription factor in regulating the development of subsets of neocortical, hippocampal, and striatal interneurons. An Lhx6 loss-of-function allele, which expresses placental alkaline phosphatase (PLAP), allowed analysis of the development and fate of Lhx6-expressing interneurons in mice lacking this homeobox transcription factor. There are Lhx6+;Dlx+ and Lhx6;Dlx+ subtypes of tangentially migrating interneurons. Most interneurons in Lhx6PLAP/PLAP mutants migrate to the cortex, although less efficiently, and exhibit defects in populating the marginal zone and superficial parts of the neocortical plate. By contrast, migration to superficial parts of the hippocampus is not seriously affected. Furthermore, whereas parvalbumin+ and somatostatin+ interneurons do not differentiate, NPY+ interneurons are present; we suggest that these NPY+ interneurons are derived from the Lhx6;Dlx+ subtype. Striatal interneurons show deficits distinct from pallial interneurons, including a reduction in the NPY+ subtype. We provide evidence that Lhx6 mediates these effects through promoting expression of receptors that regulate interneuron migration (ErbB4, CXCR4, and CXCR7), and through promoting the expression of transcription factors either known (Arx) or implicated (bMaf, Cux2, and NPAS1) in controlling interneuron development. J. Comp. Neurol. 510:79–99, 2008. © 2008 Wiley-Liss, Inc.

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