Jun Aruga, M.D., Ph.D.
- Our goal is to understand the molecular basis of higher brain functions and the pathogenesis of neurological disorders.
Behavioral and Developmental Disorders
Team Leader
Visiting Professor, Graduate School of Science & Engineering, Brain Science Institute, Saitama University
Visiting Professor, Faculty of Science and Engineering, Waseda University
Mouse disease model, Development, Transcription factor
Vertebrates have a highly organized and centralized nervous system, while the nervous system of invertebrate animals is various, ranging from the diffused nervous system in jellyfish to a moderately centralized nervous system in insects. The diversity of the nervous system is based on the genetic information that has been accumulated and sophisticated in the course of evolution. We perform comparative analysis on the structure, function and expression of genes critically involved in the neurogenesis, such as Zic, Slitrk and Lrfn, as well as other uncharacterized genes expressed in neural tissue. These analyses aim at a comprehensive understanding of the role of the genes and cis-regulatory elements in the appearance of complicated nervous system in animals. As a benefit of the comparative genomic analysis, we are developing and analyzing several model animals for neurodevelopmental disorders.
3D reconstruction of the outer surface of the brains of wild type (+/+) and Zic2 knockdown (kd/+) mice with lateral ventricle (green). Dorsal (left) and anterior-lateral (right) views are indicated. Note the enlarged lateral ventricles and the narrowed interspace between the left and right lateral ventricles containing septum (asterisk). ZIC2 has been known as a causal gene for holoprosencephaly and encodes a zinc-finger-type transcriptional regulator. We characterized Zic2 knockdown mice with a moderate (40%) reduction in Zic2 expression. Zic2 knockdown mice also showed increased locomotor activity in novel environments, cognitive and sensorimotor gating dysfunctions, and social behavioral abnormalities. Because these features are reminiscent of schizophrenia, we examined ZIC2 variant in schizophrenia patients. A novel missense mutation in ZIC2 (R409P) in schizophrenia patients was found to lower transcription-activating capacity, and to impair target DNA-binding and co-factor-binding capacities. These results warrant further study of ZIC2 in the pathogenesis of schizophrenia.
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Matsumoto Y, Katayama K, Okamoto T, Yamada K, Takashima N, Nagao S, and Aruga J: "Impaired auditory-vestibular functions and behavioral abnormalities of Slitrk6-deficient mice.", PLoS One, 6(1), e16497 (2011)
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Takashima N, Odaka YS, Sakoori K, Akagi T, Hashikawa T, Morimura N, Yamada K, and Aruga J: "Impaired cognitive function and altered hippocampal synapse morphology in mice lacking Lrrtm1, a gene associated with schizophrenia.", PLoS One, 6(7), e22716 (2011)
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Hatayama, M., Ishiguro, A., Iwayama, Y., Takashima, N., Sakoori K., Toyota, T., Nozaki, Y., Odaka, Y.S., Yamada K., Yoshikawa, T., Aruga, and J.: "Zic2 hypomorphic mutant mice as a schizophrenia model and ZIC2 mutations identified in schizophrenia patients.", Sci. Rep., 16, doi:10.1038/srep00016 (2011)
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Hatayama M, and Aruga J: "Characterization of the tandem CWCH2 sequence motif: a hallmark of inter-zinc finger interactions.", BMC Evol Biol, 10:53 (2010)
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Katayama K, Zine A, Ota M, Matsumoto Y, Inoue T, Fritzsch B, and Aruga J: "Disorganized innervation and neuronal loss in the inner ear of Slitrk6-deficient mice.", PLoS One, 4(11), e7786 (2009)
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Hatayama M, Tomizawa T, Sakai-Kato K, Bouvagnet P, Kose S, Imamoto N, Yokoyama S, Utsunomiya-Tate N, Mikoshiba K, Kigawa T, and Aruga J: "Functional and structural basis of the nuclear localization signal in the ZIC3 zinc finger domain.", Hum Mol Genet, 17(22), 3459-73 (2008)
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Katayama K, Yamada K, Ornthanalai VG, Inoue T, Ota M, Murphy NP, and Aruga J.: "Slitrk1-deficient mice display elevated anxiety-like behavior and noradrenergic abnormalities.", Mol Psychiatry, 15(2), 177-84 (2008)
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Inoue T, Ogawa M, Mikoshiba K, and Aruga J: "Zic deficiency in the cortical marginal zone and meninges results in cortical lamination defects resembling those in type II lissencephaly.", J Neurosci, 28(18), 4712-25 (2008)
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Inoue T, Ota M, Ogawa M, Mikoshiba K, and Aruga J: "Zic1 and Zic3 regulate medial forebrain development through expansion of neuronal progenitors.", J Neurosci, 27(20), 5461-73 (2007)
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Ishiguro A, Ideta M, Mikoshiba K, Chen DJ, and Aruga J: "ZIC2-dependent transcriptional regulation is mediated by DNA-dependent protein kinase, poly(ADP-ribose) polymerase, and RNA helicase A.", J Biol Chem, 282(13), 9983-95 (2007)
- Nov. 11, 2009 Identification of SLITRK6, a membrane protein that plays key roles in the formation of neuronal circuits of the inner ear Jun Aruga, M.D., Ph.D., Behavioral and Developmental Disorders
