Abstract
Disrupted-In-Schizophrenia 1 (DISC1), a susceptibility gene for major psychiatric disorders, regulates neuronal migration and differentiation during mammalian brain development. Although roles for DISC1 in postnatal neurogenesis in the dentate gyrus (DG) have recently emerged, it is not known how DISC1 and its interacting proteins govern the migration, positioning, and differentiation of dentate granule cells (DGCs). Here, we report that DISC1 interacts with the actin-binding protein girdin to regulate axonal development. DGCs in girdin-deficient neonatal mice exhibit deficits in axonal sprouting in the cornu ammonis 3 region of the hippocampus. Girdin deficiency, RNA interference-mediated knockdown, and inhibition of the DISC1/girdin interaction lead to overextended migration and mispositioning of the DGCs resulting in profound cytoarchitectural disorganization of the DG. These findings identify girdin as an intrinsic factor in postnatal development of the DG and provide insights into the critical role of the DISC1/girdin interaction in postnatal neurogenesis in the DG.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Animals, Newborn
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Bromodeoxyuridine / metabolism
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Cell Differentiation / genetics
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Cell Movement / genetics
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Cells, Cultured
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Chlorocebus aethiops
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Dentate Gyrus / cytology
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Dentate Gyrus / embryology*
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Dentate Gyrus / growth & development*
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Electric Stimulation / methods
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Embryo, Mammalian
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Gene Expression Regulation, Developmental / genetics
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Growth Cones / physiology
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Humans
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Immunoprecipitation / methods
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Membrane Potentials / drug effects
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Membrane Potentials / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microfilament Proteins / deficiency
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Microfilament Proteins / genetics
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Microfilament Proteins / metabolism*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neurogenesis / genetics
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Neurogenesis / physiology*
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Neurons / cytology
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Neurons / physiology
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Patch-Clamp Techniques
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Protein Binding
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Protein Structure, Tertiary / physiology
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RNA Interference / physiology
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Rats
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Transfection / methods
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Vesicular Transport Proteins / deficiency
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Vesicular Transport Proteins / genetics
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Vesicular Transport Proteins / metabolism*
Substances
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Disc1 protein, mouse
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Microfilament Proteins
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Nerve Tissue Proteins
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Vesicular Transport Proteins
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girdin protein, mouse
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Bromodeoxyuridine