Deficiency of CHAMP1, a gene related to intellectual disability, causes impaired neuronal development and a mild behavioural phenotype

Masayoshi Nagai; Kenji Iemura; Takako Kikkawa; Sharmin Naher; Satoko Hattori; Hideo Hagihara; Koh-Ichi Nagata; Hayato Anzawa; Risa Kugisaki; Hideki Wanibuchi; Takaya Abe; Kenichi Inoue; Kengo Kinoshita; Tsuyoshi Miyakawa; Noriko Osumi; Kozo Tanaka

doi:10.1093/braincomms/fcac220

Deficiency of CHAMP1, a gene related to intellectual disability, causes impaired neuronal development and a mild behavioural phenotype

Brain Commun. 2022 Aug 30;4(5):fcac220. doi: 10.1093/braincomms/fcac220. eCollection 2022.

Authors

Masayoshi Nagai¹, Kenji Iemura¹, Takako Kikkawa², Sharmin Naher³, Satoko Hattori⁴, Hideo Hagihara⁴, Koh-Ichi Nagata^{5

6}, Hayato Anzawa⁷, Risa Kugisaki¹, Hideki Wanibuchi⁸, Takaya Abe⁹, Kenichi Inoue⁹, Kengo Kinoshita^{7

10

11}, Tsuyoshi Miyakawa⁴, Noriko Osumi², Kozo Tanaka¹

Affiliations

¹ Department of Molecular Oncology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Miyagi 980-8575, Japan.
² Department of Developmental Neuroscience, United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
³ Department of Developmental Neuroscience, Tohoku University Graduate School of Life Sciences, Sendai, Miyagi 980-8575, Japan.
⁴ Division of Systems Medical Science, Institute for Comprehensive Medical Science (ICMS), Fujita Health University, Toyoake, Aichi 470-1192, Japan.
⁵ Department of Molecular Neurobiology, Institute of Developmental Research, Aichi Developmental Disability Center, Kasugai, Aichi 480-0392, Japan.
⁶ Department of Neurochemistry, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
⁷ Department of Applied Information Sciences, Graduate School of Information Sciences, Tohoku University, Sendai 980-8579, Japan.
⁸ Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
⁹ Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan.
¹⁰ Division of Integrated Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan.
¹¹ Department of In Silico Analysis, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan.

Abstract

CHAMP1 is a gene associated with intellectual disability, which was originally identified as being involved in the maintenance of kinetochore-microtubule attachment. To explore the neuronal defects caused by CHAMP1 deficiency, we established mice that lack CHAMP1. Mice that are homozygous knockout for CHAMP1 were slightly smaller than wild-type mice and died soon after birth on pure C57BL/6J background. Although gross anatomical defects were not found in CHAMP1 ^-/- mouse brains, mitotic cells were increased in the cerebral cortex. Neuronal differentiation was delayed in CHAMP1 ^-/- neural stem cells in vitro, which was also suggested in vivo by CHAMP1 knockdown. In a behavioural test battery, adult CHAMP1 heterozygous knockout mice showed mild memory defects, altered social interaction, and depression-like behaviours. In transcriptomic analysis, genes related to neurotransmitter transport and neurodevelopmental disorder were downregulated in embryonic CHAMP1 ^-/- brains. These results suggest that CHAMP1 plays a role in neuronal development, and CHAMP1-deficient mice resemble some aspects of individuals with CHAMP1 mutations.

Keywords: CHAMP1; behavioural tests; intellectual disability; mouse model; neuronal development.