title: DISC1 causes associative memory and neurodevelopmental defects in fruit flies.
abstract: Originally found in a Scottish family with diverse mental disorders, the DISC1 protein has been characterized as an intracellular scaffold protein that associates with diverse binding partners in neural development. To explore its functions in a genetically tractable system, we expressed the human DISC1 in fruit flies (Drosophila melanogaster). As in mammalian neurons, DISC1 is localized to diverse subcellular domains of developing fly neurons including the nuclei, axons and dendrites. Overexpression of DISC1 impairs associative memory. Experiments with deletion/mutation constructs have revealed the importance of amino-terminal domain (46-290) for memory suppression whereas carboxyl domain (598-854) and the amino-terminal residues (1-45) including the nuclear localization signal (NLS1) are dispensable. DISC1 overexpression also causes suppression of axonal and dendritic branching of mushroom body neurons, which mediate a variety of cognitive functions in the fly brain. Analyses with deletion/mutation constructs reveal that protein domains 598-854 and 349-402 are both required for the suppression of axonal branching, while amino-terminal domains including NLS1 are dispensable. In contrast, NLS1 was required for the suppression of dendritic branching, suggesting a mechanism involving gene expression. Moreover, domain 403-596 is also required for the suppression of dendritic branching. We also show that overexpression of DISC1 suppresses glutamatergic synaptogenesis in developing neuromuscular junctions. Deletion/mutation experiments have revealed the importance of protein domains 403-596 and 349-402 for synaptic suppression, while amino-terminal domains including NLS1 are dispensable. Finally, we show that DISC1 functionally interacts with the fly homolog of Dysbindin (DTNBP1) via direct protein-protein interaction in developing synapses.
authors.affiliation: Life and Environmental Sciences, Institute of Biological Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Furukubo-Tokunaga
authors.affiliation: Life and Environmental Sciences, Institute of Biological Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kurita
authors.affiliation: Life and Environmental Sciences, Institute of Biological Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Honjo
authors.affiliation: Life and Environmental Sciences, Institute of Biological Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Pandey
authors.affiliation: Life and Environmental Sciences, Institute of Biological Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ando
authors.affiliation: Life and Environmental Sciences, Institute of Biological Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Takayama
authors.affiliation: Life and Environmental Sciences, Institute of Biological Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Life and Environmental Sciences, Institute of Biological Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Mochizuki
authors.affiliation: Life and Environmental Sciences, Institute of Biological Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ando
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kamiya
authors.affiliation: Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sawa
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics; D001369:Axons / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins / Q000378:metabolism; D006801:Humans; D008568:Memory / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D065886:Neurodevelopmental Disorders / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D000072417:Protein Domains / Q000235:genetics; D013569:Synapses / Q000235:genetics / Q000378:metabolism
chemical_list: C412476:DISC1 protein, human; D029721:Drosophila Proteins; C569104:Dysb protein, Drosophila; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D009419:Nerve Tissue Proteins