DISC1 causes associative memory and neurodevelopmental defects in fruit flies

Furukubo-Tokunaga, Katsuo; Kurita, Kazuki; Honjo, Ken; Pandey, Himani; Ando, Tetsuya; Takayama, Kojiro; Arai, Yūkō; Mochizuki, Hitoshi; Ando, Masao; Kamiya, Atsushi; Sawa, Akira

doi:10.1038/mp.2016.15

Cited by 18 publications

(23 citation statements)

References 83 publications

(127 reference statements)

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“…Nonetheless, the biological impact of DISC1 deficits in the Scottish pedigree is not yet perfectly understood. We have reported that transgenic Drosophila expressing wildtype (WT) human DISC1 in the mushroom body (a gain of function model) show several abnormalities, including disturbance in sleep homeostasis (Sawamura et al, 2008; Furukubo-Tokunaga et al, 2016). Here we generated transgenic mice that express WT human DISC1.…”

Section: Introductionmentioning

confidence: 99%

Abnormal wake/sleep pattern in a novel gain-of-function model of DISC1

Jaaro-Peled

Altimus

LeGates

et al. 2016

Neuroscience Research

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Sleep disturbances are common in psychiatric disorders, but the causal relationship between the two and the underlying genetic factors is unclear. The DISC1 gene is strongly linked to mood disorders and schizophrenia in a Scottish pedigree. In an earlier study we found a sleep homeostasis disturbance in a Drosophila model overexpressing wild-type human DISC1. Here we aimed to explore the relationship between sleep and the DISC1 gene in a mammalian model, a novel transgenic mouse model expressing full-length human DISC1.We assessed circadian rhythms by monitoring wheel running activity under normal 24-h light:dark conditions and in constant darkness and found the DISC1 mice to have normal circadian photoentrainment and normal intrinsic circadian period. We also assessed sleep duration and quality in the DISC1 mice and found that they were awake longer than wild-type controls at baseline with a tendency for lower rebound of delta activity during recovery from a short sleep deprivation. Thus we suggest that DISC1 may be involved in sleep regulation.

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Section: Introductionmentioning

confidence: 99%

Abnormal wake/sleep pattern in a novel gain-of-function model of DISC1

Jaaro-Peled

Altimus

LeGates

et al. 2016

Neuroscience Research

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“…The following observations support this contention. First, dysbindin interacts with DISC1 at the synapse (Furukubo‐Tokunaga et al, ). DISC1 is a gene mutated in neuropsychiatric and neurodevelopmental disorders, and it is required for neuronal development and synapse function (Blackwood et al, ; Kilpinen et al, ; Crepel et al, ; Porteous et al, ; Wen et al, ).…”

Section: Neurodevelopmental Disorders Associated To Bloc‐1 and Borc Cmentioning

confidence: 99%

“…The following observations support this contention. First, dysbindin interacts with DISC1 at the synapse (Furukubo-Tokunaga et al, 2016a, 2016b. DISC1 is a gene mutated in neuropsychiatric and neurodevelopmental disorders, and it is required for neuronal development and synapse function Figure 3 Deleterious mutations in genes from BLOC-1, BORC, and primary cilia interactomes in schizophrenia patients.…”

Section: Neurodevelopmental Disorders Associated To Bloc-1 and Borc Cmentioning

confidence: 99%

“…3C) (Schizophrenia Working Group of the Psychiatric Genomics, 2014). DICS1 gene defects were identified in a large pedigree affected by psychiatric pathology (Furukubo-Tokunaga et al, 2016a, 2016b. Mutations on DISC1 alter synaptic vesicle recycling and generate schizophrenia endophenotypes in mice (Porteous et al, 2011;Wen et al, 2014;Tomoda et al, 2016).…”

Section: Primary Cilia and Its Implications For The Dopaminergic And mentioning

confidence: 99%

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Neurodevelopmental disease mechanisms, primary cilia, and endosomes converge on the BLOC‐1 and BORC complexes

Hartwig

Monis

Chen

et al. 2017

Developmental Neurobiology

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The biogenesis of lysosome-related organelles complex-1 (BLOC-1) and the bloc-one-related complex (BORC) are the cytosolic protein complexes required for specialized membrane protein traffic along the endocytic route and the spatial distribution of endosome-derived compartments, respectively. BLOC-1 and BORC complex subunits and components of their interactomes have been associated with the risk and/or pathomechanisms of neurodevelopmental disorders. Thus, cellular processes requiring BLOC-1 and BORC interactomes have the potential to offer novel insight into mechanisms underlying behavioral defects. We focus on interactions between BLOC-1 or BORC subunits with the actin and microtubule cytoskeleton, membrane tethers, and SNAREs. These interactions highlight requirements for BLOC-1 and BORC in membrane movement by motors, control of actin polymerization, and targeting of membrane proteins to specialized cellular domains such as the nerve terminal and the primary cilium. We propose that the endosome-primary cilia pathway is an underappreciated hub in the genesis and mechanisms of neurodevelopmental disorders. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 311-330, 2018.

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“…To analyze genetic interactions of DISC1 and psychiatric risk factor genes, we have introduced the human DISC1 gene in fruit flies to be expressed in their nervous system. We showed previously 27 that overexpression of DISC1 ( DISC1 OE ) suppresses synaptogenesis at the developing larval NMJs. In this work, we conducted a systematic screening for interacting risk factor genes that cooperatively function with DISC1 to cause modification of the synaptic phenotypes.…”

Section: Introductionmentioning

confidence: 98%

Genetic interaction of DISC1 and Neurexin in the development of fruit fly glutamatergic synapses

et al. 2017

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Originally identified at the breakpoint of a (1;11)(q42.1; q14.3) chromosomal translocation in a Scottish family with a wide range of mental disorders, the DISC1 gene has been a focus of intensive investigations as an entry point to study the molecular mechanisms of diverse mental dysfunctions. Perturbations of the DISC1 functions lead to behavioral changes in animal models, which are relevant to psychiatric conditions in patients. In this work, we have expressed the human DISC1 gene in the fruit fly (Drosophila melanogaster) and performed a genetic screening for the mutations of psychiatric risk genes that cause modifications of DISC1 synaptic phenotypes at the neuromuscular junction. We found that DISC1 interacts with dnrx1, the Drosophila homolog of the human Neurexin (NRXN1) gene, in the development of glutamatergic synapses. While overexpression of DISC1 suppressed the total bouton area on the target muscles and stimulated active zone density in wild-type background, a partial reduction of the dnrx1 activity negated the DISC1–mediated synaptic alterations. Likewise, overexpression of DISC1 stimulated the expression of a glutamate receptor component, DGLURIIA, in wild-type background but not in the dnrx1 heterozygous background. In addition, DISC1 caused mislocalization of Discs large, the Drosophila PSD-95 homolog, in the dnrx1 heterozygous background. Analyses with a series of domain deletions have revealed the importance of axonal localization of the DISC1 protein for efficient suppression of DNRX1 in synaptic boutons. These results thus suggest an intriguing converging mechanism controlled by the interaction of DISC1 and Neurexin in the developing glutamatergic synapses.

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DISC1 causes associative memory and neurodevelopmental defects in fruit flies

Cited by 18 publications

References 83 publications

Abnormal wake/sleep pattern in a novel gain-of-function model of DISC1

Abnormal wake/sleep pattern in a novel gain-of-function model of DISC1

Neurodevelopmental disease mechanisms, primary cilia, and endosomes converge on the BLOC‐1 and BORC complexes

Genetic interaction of DISC1 and Neurexin in the development of fruit fly glutamatergic synapses

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