Dixdc1 Is a Critical Regulator of DISC1 and Embryonic Cortical Development
Copyright policy )Dixdc1 Is a Critical Regulator of DISC1 and Embryonic Cortical Development
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.
- Columbia University United States
- Massachusetts Institute of Technology United States
- King’s University United States
- Broad Institute United States
- Picower Institute for Learning and Memory United States
Neuroscience(all), Green Fluorescent Proteins, Cell Cycle Proteins, Nerve Tissue Proteins, MOLNEURO, DEVELOPMENT, Mice, Cell Movement, Animals, Humans, Cells, Cultured, Cell Proliferation, Cerebral Cortex, Microfilament Proteins, Intracellular Signaling Peptides and Proteins, Gene Expression Regulation, Developmental, Embryo, Mammalian, Luminescent Proteins, Electroporation, Animals, Newborn, Bromodeoxyuridine, Female, Microtubule-Associated Proteins
Neuroscience(all), Green Fluorescent Proteins, Cell Cycle Proteins, Nerve Tissue Proteins, MOLNEURO, DEVELOPMENT, Mice, Cell Movement, Animals, Humans, Cells, Cultured, Cell Proliferation, Cerebral Cortex, Microfilament Proteins, Intracellular Signaling Peptides and Proteins, Gene Expression Regulation, Developmental, Embryo, Mammalian, Luminescent Proteins, Electroporation, Animals, Newborn, Bromodeoxyuridine, Female, Microtubule-Associated Proteins
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