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Dormant state of quiescent neural stem cells links Shank3 mutation to autism development

Molecular Psychiatry volume 27, pages 2751–2765 (2022)Cite this article

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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.

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Fig. 1: Identification of qNSCs as a target cell for aberrant neurodevelopment in the Shank3 deficient autistic mouse brain.
Fig. 2: Validation of qNSCs activity in the SVZ and dentate gyrus of Shank3B deficient mice.
Fig. 3: Dormant state of qNSCs as a target for aberrant neurodevelopment in the Shank3 deficient autistic mouse brain.
Fig. 4: Inhibition of Kmt2a rescues the abnormal quiescent state of qNSCs and autism-like social deficits of Shank3 deficient mice.
Fig. 5: OICR-9429 induces activation of abnormal quiescent state of qNSCs and prolonged rescue of autism-like social deficits in Shank3B KO mice.
Fig. 6: Targeting human qNSCs activity in SHANK3-deficient human NSCs and autistic patient brains.

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Data availability

The analysis of single-cell RNA-seq and ATAC-seq data reported in this paper has been deposited in the NCBI SRA database.

Code availability

All codes generated in this study are available from the lead contact upon reasonable request.

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Acknowledgements

This work was supported by the National Research Foundation of Korea by the Ministry of Education, Science, and Technology (NRF-2020R1A2C3007378, 2021M3E5E5096464). This work is also supported by Lundbeck Foundation (R313–2019–421) and The Novo Nordisk Foundation Center (NNF17CC0027852) to KJW.

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  1. These authors contributed equally: Hongwon Kim, Byounggook Cho, Hanseul Park.

Authors and Affiliations

  1. Laboratory of Stem Cells & Cell Reprogramming, Department of Chemistry and Biomedical Engineering, Dongguk University, Seoul, 04620, Republic of Korea

    Hongwon Kim, Byounggook Cho, Hanseul Park, Junyeop Kim, Siyoung Kim, Jaein Shin & Jongpil Kim

  2. Department of Biomedical Sciences, School of Veterinary Medicine and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Christopher J. Lengner

  3. Biotech Research and Innovation Centre (BRIC) and Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen, Denmark

    Kyoung-Jae Won

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HK and BC performed the experiments. CJL, and KJW performed the data analysis. HK, BC, and JK designed the study and contributed to writing the paper.

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Correspondence to Kyoung-Jae Won or Jongpil Kim.

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Kim, H., Cho, B., Park, H. et al. Dormant state of quiescent neural stem cells links Shank3 mutation to autism development. Mol Psychiatry 27, 2751–2765 (2022). https://doi.org/10.1038/s41380-022-01563-1

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