TY - JOUR
T1 - Abnormal Behavior in a Chromosome- Engineered Mouse Model for Human 15q11-13 Duplication Seen in Autism
AU - Nakatani, Jin
AU - Tamada, Kota
AU - Hatanaka, Fumiyuki
AU - Ise, Satoko
AU - Ohta, Hisashi
AU - Inoue, Kiyoshi
AU - Tomonaga, Shozo
AU - Watanabe, Yasuhito
AU - Chung, Yeun Jun
AU - Banerjee, Ruby
AU - Iwamoto, Kazuya
AU - Kato, Tadafumi
AU - Okazawa, Makoto
AU - Yamauchi, Kenta
AU - Tanda, Koichi
AU - Takao, Keizo
AU - Miyakawa, Tsuyoshi
AU - Bradley, Allan
AU - Takumi, Toru
N1 - Funding Information:
T.T. acknowledges M. Young for discussions that led to start this project and K. Tanaka, O. Hayaishi, H. Hanafusa, and S. Nakanishi for general support. The authors thank K. Sakimura and M. Abe for their help in the initial stage of this study; N. Nakai, A. Yamamoto, T. Sudo, F. Law, A. Beasley, E. Grau, T. Hamilton, L. Davis, H. Kitson, H. Ogino, and R. Takayama for technical assistance; W. Wang, D. Adams, N. Conte, T. Kishino, T. Manabe, and P. Levitt for valuable comments; and all members of the Takumi laboratory. We also thank K. Nakao and members of Animal Resource Unit, RIKEN Center for Developmental Biology, for breeding of mice. J.N. and S.T. were supported by a Japan Society for the Promotion of Science fellowship. This work was supported in part by a grant from the Grants-in-Aid for Scientific Research on Priority Areas-Research on Pathomechanisms of Brain Disorders from the Ministry of Education, Culture, Sports, Science and Technology, the Neuroinformatics Japan Center, the Institute for Bioinformatics Research and Development, and Core Research for Evolutional Science and Technology of the Japan Science and Technology Agency, and by research grants from the Mitsubishi Foundation, the Mother and Child Health Foundation, the Mitsubishi Pharma Research Foundation, the Takeda Science Foundation, the Astellas Foundation for Research on Metabolic Disorders, Sony Corporation, Nippon Boehringer Ingelheim Co., Ltd, and the Wellcome Trust.
PY - 2009/6/26
Y1 - 2009/6/26
N2 - Substantial evidence suggests that chromosomal abnormalities contribute to the risk of autism. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We have modeled this genetic change in mice by using chromosome engineering to generate a 6.3 Mb duplication of the conserved linkage group on mouse chromosome 7. Mice with a paternal duplication display poor social interaction, behavioral inflexibility, abnormal ultrasonic vocalizations, and correlates of anxiety. An increased MBII52 snoRNA within the duplicated region, affecting the serotonin 2c receptor (5-HT2cR), correlates with altered intracellular Ca2+ responses elicited by a 5-HT2cR agonist in neurons of mice with a paternal duplication. This chromosome-engineered mouse model for autism seems to replicate various aspects of human autistic phenotypes and validates the relevance of the human chromosome abnormality. This model will facilitate forward genetics of developmental brain disorders and serve as an invaluable tool for therapeutic development.
AB - Substantial evidence suggests that chromosomal abnormalities contribute to the risk of autism. The duplication of human chromosome 15q11-13 is known to be the most frequent cytogenetic abnormality in autism. We have modeled this genetic change in mice by using chromosome engineering to generate a 6.3 Mb duplication of the conserved linkage group on mouse chromosome 7. Mice with a paternal duplication display poor social interaction, behavioral inflexibility, abnormal ultrasonic vocalizations, and correlates of anxiety. An increased MBII52 snoRNA within the duplicated region, affecting the serotonin 2c receptor (5-HT2cR), correlates with altered intracellular Ca2+ responses elicited by a 5-HT2cR agonist in neurons of mice with a paternal duplication. This chromosome-engineered mouse model for autism seems to replicate various aspects of human autistic phenotypes and validates the relevance of the human chromosome abnormality. This model will facilitate forward genetics of developmental brain disorders and serve as an invaluable tool for therapeutic development.
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U2 - 10.1016/j.cell.2009.04.024
DO - 10.1016/j.cell.2009.04.024
M3 - Article
C2 - 19563756
AN - SCOPUS:67549083336
SN - 0092-8674
VL - 137
SP - 1235
EP - 1246
JO - Cell
JF - Cell
IS - 7
ER -