TY - JOUR
T1 - Dixdc1 is a critical regulator of disc1 and embryonic cortical development
AU - Singh, Karun K.
AU - Ge, Xuecai
AU - Mao, Yingwei
AU - Drane, Laurel
AU - Meletis, Konstantinos
AU - Samuels, Benjamin A.
AU - Tsai, Li Huei
N1 - Funding Information:
We would like to thank Z. Xie for the S/A-β-catenin and pNeuroD-GFP constructs. We would like to thank Takahiro Soda and Alison Mungenast for critical reading of the manuscript, and all other Tsai lab members. L.-H. T. is an investigator of the Howard Hughes Medical Institute and the director of the neurobiology program at the Stanley Center for Psychiatric Research. K.K.S. is a recipient of the Human Frontiers Science Program Longterm fellowship and an NSERC postdoctoral fellowship. Y.M. is a recipient of the National Alliance for Research on Schizophrenia and Depression Young Investigator Award. This work was partially supported by a National Institutes of Health grant (NS37007) to L.-H.T.
PY - 2010/7
Y1 - 2010/7
N2 - 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-GSK3β/β-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-GSK3β/β-catenin-dependent and -independent signaling pathways during cortical development and further delineate how DISC1 contributes to neuropsychiatric disorders.
AB - 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-GSK3β/β-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-GSK3β/β-catenin-dependent and -independent signaling pathways during cortical development and further delineate how DISC1 contributes to neuropsychiatric disorders.
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U2 - 10.1016/j.neuron.2010.06.002
DO - 10.1016/j.neuron.2010.06.002
M3 - Article
C2 - 20624590
AN - SCOPUS:77954504217
SN - 0896-6273
VL - 67
SP - 33
EP - 48
JO - Neuron
JF - Neuron
IS - 1
ER -