Abstract
The psychiatric illness risk gene Disrupted in Schizophrenia-1 (DISC1) plays an important role in brain development; however, it is unclear how DISC1 is regulated during cortical development. Here, we report that DISC1 is regulated during embryonic neural progenitor proliferation and neuronal migration through an interaction with DIX domain containing-1 (Dixdc1), the third mammalian gene discovered to contain a Disheveled-Axin (DIX) domain. We determined that Dixdc1 functionally interacts with DISC1 to regulate neural progenitor proliferation by co-modulating Wnt-GSK3beta/beta-catenin signaling. However, DISC1 and Dixdc1 do not regulate migration via this pathway. During neuronal migration, we discovered that phosphorylation of Dixdc1 by cyclin-dependent kinase 5 (Cdk5) facilitates its interaction with the DISC1-binding partner Ndel1. Furthermore, Dixdc1 phosphorylation and its interaction with DISC1/Ndel1 in vivo is required for neuronal migration. Together, these data reveal that Dixdc1 integrates DISC1 into Wnt-GSK3beta/beta-catenin-dependent and -independent signaling pathways during cortical development and further delineate how DISC1 contributes to neuropsychiatric disorders.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Bromodeoxyuridine / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Movement / genetics
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Cell Movement / physiology
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Cell Proliferation
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Cells, Cultured
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Cerebral Cortex / cytology
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Cerebral Cortex / embryology*
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Electroporation / methods
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Embryo, Mammalian
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Female
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Gene Expression Regulation, Developmental / physiology
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Green Fluorescent Proteins / genetics
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Luminescent Proteins / genetics
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Mice
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Microfilament Proteins / genetics
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Microfilament Proteins / metabolism*
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Microtubule-Associated Proteins
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Neurons / physiology*
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Pregnancy
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Protein Binding / genetics
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RNA Interference / physiology
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Stem Cells / physiology
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Transfection / methods
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Wnt Proteins / genetics
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Wnt Proteins / metabolism
Substances
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Cell Cycle Proteins
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DISC1 protein, human
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DIXDC1 protein, human
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Intracellular Signaling Peptides and Proteins
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Luminescent Proteins
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Microfilament Proteins
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Microtubule-Associated Proteins
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Nde1 protein, mouse
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Nerve Tissue Proteins
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Wnt Proteins
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enhanced green fluorescent protein
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Green Fluorescent Proteins
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Bromodeoxyuridine