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, Jin Wu Tsai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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.

Original languageEnglish
Article number2498
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - 1 Dec 2018

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