TY - JOUR
T1 - Increased L1 retrotransposition in the neuronal genome in schizophrenia
AU - Bundo, Miki
AU - Toyoshima, Manabu
AU - Okada, Yohei
AU - Akamatsu, Wado
AU - Ueda, Junko
AU - Nemoto-Miyauchi, Taeko
AU - Sunaga, Fumiko
AU - Toritsuka, Michihiro
AU - Ikawa, Daisuke
AU - Kakita, Akiyoshi
AU - Kato, Motoichiro
AU - Kasai, Kiyoto
AU - Kishimoto, Toshifumi
AU - Nawa, Hiroyuki
AU - Okano, Hideyuki
AU - Yoshikawa, Takeo
AU - Kato, Tadafumi
AU - Iwamoto, Kazuya
N1 - Funding Information:
This work was supported in part by the Grant-in-Aid for Scientific Research on Innovative Areas (Unraveling the microendophenotypes of psychiatric disorders at the molecular, cellular, and circuit levels) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to T.Y., H.N., T.K., and K.I., and a Grant-in-Aid from Ministry of Health, Labour and Welfare to T.K. This work was also supported by JST, CREST to T.K. and by JST, PRESTO to K.I. This work was also supported in part by Leading Project for Realization of Regenerative Medicine from MEXT and “Funding Program for World-Leading Innovative R&D on Science and Technology” to H.O., and by the “Development of biomarker candidates for social behavior” carried out under the Strategic Research Program for Brain Sciences from MEXT to T.Y. and K.K. This work was also supported in part by the Collaborative Research Project of the Brain Research Institute, Niigata University . Postmortem samples were donated by the Stanley Medical Research Institute, courtesy of Drs. Michael B. Knable, E. Fuller Torrey, Maree J. Webster, and Robert H. Yolken. We thank Tomoko Toyota and Atsuko Komori-Kokubo at RIKEN BSI for their technical assistance. We also thank Kenji Ohtawa at Research Resources Center at the RIKEN BSI for the cell-sorting analysis. M.B., F.S., and K.I. belong to the Department of Molecular Psychiatry, which is endowed by Dainippon Sumitomo Pharma and Yoshitomiyakuhin. H.O. is a scientific consultant for San Bio, Eisai, and Daiichi Sankyo. T.K. received a grant from Takeda Pharmaceutical . These companies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PY - 2014/1/22
Y1 - 2014/1/22
N2 - Recent studies indicate that long interspersed nuclear element-1 (L1) are mobilized in the genome of human neural progenitor cells and enhanced in Rett syndrome and ataxia telangiectasia. However, whether aberrant L1 retrotransposition occurs in mental disorders is unknown. Here, we report high L1 copy number in schizophrenia. Increased L1 was demonstrated in neurons from prefrontal cortex of patients and in induced pluripotent stem (iPS) cell-derived neurons containing 22q11 deletions. Whole-genome sequencing revealed brain-specific L1 insertion in patients localized preferentially to synapse- and schizophrenia-related genes. To study the mechanism of L1 transposition, we examined perinatal environmental risk factors for schizophrenia in animal models and observed an increased L1 copy number after immune activation by poly-I:C or epidermal growth factor. These findings suggest that hyperactive retrotransposition of L1 in neurons triggered by environmental and/or genetic risk factors may contribute to the susceptibility and pathophysiology of schizophrenia.
AB - Recent studies indicate that long interspersed nuclear element-1 (L1) are mobilized in the genome of human neural progenitor cells and enhanced in Rett syndrome and ataxia telangiectasia. However, whether aberrant L1 retrotransposition occurs in mental disorders is unknown. Here, we report high L1 copy number in schizophrenia. Increased L1 was demonstrated in neurons from prefrontal cortex of patients and in induced pluripotent stem (iPS) cell-derived neurons containing 22q11 deletions. Whole-genome sequencing revealed brain-specific L1 insertion in patients localized preferentially to synapse- and schizophrenia-related genes. To study the mechanism of L1 transposition, we examined perinatal environmental risk factors for schizophrenia in animal models and observed an increased L1 copy number after immune activation by poly-I:C or epidermal growth factor. These findings suggest that hyperactive retrotransposition of L1 in neurons triggered by environmental and/or genetic risk factors may contribute to the susceptibility and pathophysiology of schizophrenia.
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U2 - 10.1016/j.neuron.2013.10.053
DO - 10.1016/j.neuron.2013.10.053
M3 - Article
C2 - 24389010
AN - SCOPUS:84892789989
SN - 0896-6273
VL - 81
SP - 306
EP - 313
JO - Neuron
JF - Neuron
IS - 2
ER -