한빛사논문
- 조회670
Hongwon Kim1,4, Byounggook Cho1,4, Hanseul Park1,4, Junyeop Kim1, Siyoung Kim1, Jaein Shin1, Christopher J. Lengner2, Kyoung-Jae Won3,* and Jongpil Kim1,*
1Laboratory of Stem Cells & Cell Reprogramming, Department of Chemistry and Biomedical Engineering, Dongguk University, Seoul 04620, Republic of Korea. 2Department of Biomedical Sciences, School of Veterinary Medicine and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. 3Biotech Research and Innovation Centre (BRIC) and Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen, Denmark.
4These authors contributed equally: Hongwon Kim, Byounggook Cho, Hanseul Park
*Corresponding author.
Abstract
Autism spectrum disorders (ASDs) are common neurodevelopmental disorders characterized by deficits in social interactions and communication, restricted interests, and repetitive behaviors. Despite extensive study, the molecular targets that control ASD development remain largely unclear. Here, we report that the dormancy of quiescent neural stem cells (qNSCs) is a therapeutic target for controlling the development of ASD phenotypes driven by Shank3 deficiency. Using single-cell RNA sequencing (scRNA-seq) and transposase accessible chromatin profiling (ATAC-seq), we find that abnormal epigenetic features including H3K4me3 accumulation due to up-regulation of Kmt2a levels lead to increased dormancy of qNSCs in the absence of Shank3. This result in decreased active neurogenesis in the Shank3 deficient mouse brain. Remarkably, pharmacological and molecular inhibition of qNSC dormancy restored adult neurogenesis and ameliorated the social deficits observed in Shank3-deficient mice. Moreover, we confirmed restored human qNSC activity rescues abnormal neurogenesis and autism-like phenotypes in SHANK3-targeted human NSCs. Taken together, our results offer a novel strategy to control qNSC activity as a potential therapeutic target for the development of autism.
논문정보
- Research article
- 2022년 04월 (BRIC 등록일 2022-04-22)
- 국내(교신)+국외 연구진
- 생명과학 > 신경생물학
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