DISC1 regulates primary cilia that display specific dopamine receptors.
BACKGROUND
Mutations in the DISC1 gene are strongly associated with major psychiatric syndromes such as schizophrenia. DISC1 encodes a cytoplasmic protein with many potential interaction partners, but its cellular functions remain poorly understood. We identified a role of DISC1 in the cell biology of primary cilia that display disease-relevant dopamine receptors.


RESULTS
A GFP-tagged DISC1 construct expressed in NIH3T3 cells and rat striatal neurons localized near the base of primary cilia. RNAi-mediated knockdown of endogenous DISC1 resulted in a marked reduction in the number of cells expressing a primary cilium. FLAG-tagged versions of the cloned human D1, D2 and D5 dopamine receptors concentrated highly on the ciliary surface, and this reflects a specific targeting mechanism specific because D3 and D4 receptors localized to the plasma membrane but were not concentrated on cilia.


CONCLUSIONS
These results identify a role of DISC1 in regulating the formation and/or maintenance of primary cilia, and establish subtype-specific targeting of dopamine receptors to the ciliary surface. Our findings provide new insight to receptor cell biology and suggest a relationship between DISC1 and neural dopamine signaling.
Department of Psychiatry, University of California San Francisco, San Francisco, California, United States of America.
Aaron
A
Marley
Mark
M
von Zastrow
D000818:Animals; D002923:Cilia / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D011954:Receptors, Dopamine / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013499:Surface Properties
C412476:DISC1 protein, human; C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; D011954:Receptors, Dopamine; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins