Abnormal Behavior in a Chromosome- Engineered Mouse Model for Human 15q11-13 Duplication Seen in Autism

Jin Nakatani, Kota Tamada, Fumiyuki Hatanaka, Satoko Ise, Hisashi Ohta, Kiyoshi Inoue, Shozo Tomonaga, Yasuhito Watanabe, Yeun Jun Chung, Ruby Banerjee, Kazuya Iwamoto, Tadafumi Kato, Makoto Okazawa, Kenta Yamauchi, Koichi Tanda, Keizo Takao, Tsuyoshi Miyakawa, Allan Bradley, Toru Takumi

Research output: Contribution to journalArticle

285 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1235-1246
Number of pages12
JournalCell
Volume137
Issue number7
DOIs
Publication statusPublished - 26-06-2009

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Chromosomes
Autistic Disorder
Chromosome Aberrations
Human Chromosomes
Small Nucleolar RNA
Receptor, Serotonin, 5-HT2C
Chromosomes, Human, Pair 13
Chromosomes, Human, Pair 7
Brain Diseases
Interpersonal Relations
Ultrasonics
Neurons
Brain
Anxiety
Phenotype
Therapeutics

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Nakatani, J., Tamada, K., Hatanaka, F., Ise, S., Ohta, H., Inoue, K., ... Takumi, T. (2009). Abnormal Behavior in a Chromosome- Engineered Mouse Model for Human 15q11-13 Duplication Seen in Autism. Cell, 137(7), 1235-1246. https://doi.org/10.1016/j.cell.2009.04.024
Nakatani, Jin ; Tamada, Kota ; Hatanaka, Fumiyuki ; Ise, Satoko ; Ohta, Hisashi ; Inoue, Kiyoshi ; Tomonaga, Shozo ; Watanabe, Yasuhito ; Chung, Yeun Jun ; Banerjee, Ruby ; Iwamoto, Kazuya ; Kato, Tadafumi ; Okazawa, Makoto ; Yamauchi, Kenta ; Tanda, Koichi ; Takao, Keizo ; Miyakawa, Tsuyoshi ; Bradley, Allan ; Takumi, Toru. / Abnormal Behavior in a Chromosome- Engineered Mouse Model for Human 15q11-13 Duplication Seen in Autism. In: Cell. 2009 ; Vol. 137, No. 7. pp. 1235-1246.
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Nakatani, J, Tamada, K, Hatanaka, F, Ise, S, Ohta, H, Inoue, K, Tomonaga, S, Watanabe, Y, Chung, YJ, Banerjee, R, Iwamoto, K, Kato, T, Okazawa, M, Yamauchi, K, Tanda, K, Takao, K, Miyakawa, T, Bradley, A & Takumi, T 2009, 'Abnormal Behavior in a Chromosome- Engineered Mouse Model for Human 15q11-13 Duplication Seen in Autism', Cell, vol. 137, no. 7, pp. 1235-1246. https://doi.org/10.1016/j.cell.2009.04.024

Abnormal Behavior in a Chromosome- Engineered Mouse Model for Human 15q11-13 Duplication Seen in Autism. / Nakatani, Jin; Tamada, Kota; Hatanaka, Fumiyuki; Ise, Satoko; Ohta, Hisashi; Inoue, Kiyoshi; Tomonaga, Shozo; Watanabe, Yasuhito; Chung, Yeun Jun; Banerjee, Ruby; Iwamoto, Kazuya; Kato, Tadafumi; Okazawa, Makoto; Yamauchi, Kenta; Tanda, Koichi; Takao, Keizo; Miyakawa, Tsuyoshi; Bradley, Allan; Takumi, Toru.

In: Cell, Vol. 137, No. 7, 26.06.2009, p. 1235-1246.

Research output: Contribution to journalArticle

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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

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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