Identification of genes associated with cortical malformation using a transposon-mediated somatic mutagenesis screen in mice

I-Ling Lu, Chien Chen, Chien-Yi Tung, Hsin-Hung Chen, Jia-Ping Pan, Chia-Hsiang Chang, Jia-Shing Cheng, Yi-An Chen, Chun-Hung Wang, Chia-Wei Huang, Yi-Ning Kang, Hsin-Yun Chang, Lei-Li Li, Kai-Ping Chang, Yang-Hsin Shih, Chi-Hung Lin, Shang-Yeong Kwan and Jin-Wu Tsai ()
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I-Ling Lu: National Yang-Ming University
Chien Chen: Taipei Veterans General Hospital
Chien-Yi Tung: VYM Genome Research Center of National Yang-Ming University
Hsin-Hung Chen: National Yang-Ming University School of Medicine
Jia-Ping Pan: VYM Genome Research Center of National Yang-Ming University
Chia-Hsiang Chang: National Yang-Ming University
Jia-Shing Cheng: National Yang-Ming University
Yi-An Chen: National Yang-Ming University
Chun-Hung Wang: National Yang-Ming University
Chia-Wei Huang: National Yang-Ming University
Yi-Ning Kang: National Yang-Ming University
Hsin-Yun Chang: National Yang-Ming University
Lei-Li Li: National Yang-Ming University
Kai-Ping Chang: National Yang-Ming University School of Medicine
Yang-Hsin Shih: National Yang-Ming University School of Medicine
Chi-Hung Lin: VYM Genome Research Center of National Yang-Ming University
Shang-Yeong Kwan: Taipei Veterans General Hospital
Jin-Wu Tsai: National Yang-Ming University

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Mutations in genes involved in the production, migration, or differentiation of cortical neurons often lead to malformations of cortical development (MCDs). However, many genetic mutations involved in MCD pathogenesis remain unidentified. Here we developed a genetic screening paradigm based on transposon-mediated somatic mutagenesis by in utero electroporation and the inability of mutant neuronal precursors to migrate to the cortex and identified 33 candidate MCD genes. Consistent with the screen, several genes have already been implicated in neural development and disorders. Functional disruption of the candidate genes by RNAi or CRISPR/Cas9 causes altered neuronal distributions that resemble human cortical dysplasia. To verify potential clinical relevance of these candidate genes, we analyzed somatic mutations in brain tissue from patients with focal cortical dysplasia and found that mutations are enriched in these candidate genes. These results demonstrate that this approach is able to identify potential mouse genes involved in cortical development and MCD pathogenesis.

Date: 2018
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DOI: 10.1038/s41467-018-04880-8

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