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.
Singh
Karun K
KK
Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Ge
Xuecai
X
Mao
Yingwei
Y
Drane
Laurel
L
Meletis
Konstantinos
K
Samuels
Benjamin A
BA
Tsai
Li-Huei
LH
D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology*; D018274:Electroporation / Q000379:methods; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D011247:Pregnancy; D011485:Protein Binding / Q000235:genetics; D034622:RNA Interference / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013234:Stem Cells / Q000502:physiology; D014162:Transfection / Q000379:methods; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; C412476:DISC1 protein, human; C513335:DIXDC1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; C531336:Nde1 protein, mouse; D009419:Nerve Tissue Proteins; D051153:Wnt Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D001973:Bromodeoxyuridine