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DPYSL2/CRMP2 isoform B knockout in human iPSC-derived glutamatergic neurons confirms its role in mTOR signaling and neurodevelopmental disorders

Molecular Psychiatry volume 28, pages 4353–4362 (2023)Cite this article

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Abstract

The DPYSL2/CRMP2 gene encodes a microtubule-stabilizing protein crucial for neurogenesis and is associated with numerous psychiatric and neurodegenerative disorders including schizophrenia, bipolar disorder, and Alzheimer’s disease. DPYSL2 generates multiple RNA and protein isoforms, but few studies have differentiated between them. We previously reported an association of a functional variant in the DPYSL2-B isoform with schizophrenia (SCZ) and demonstrated in HEK293 cells that this variant reduced the length of cellular projections and created transcriptomic changes that captured schizophrenia etiology by disrupting mTOR signaling-mediated regulation. In the present study, we follow up on these results by creating, to our knowledge, the first models of endogenous DPYSL2-B knockout in human induced pluripotent stem cells (iPSCs) and neurons. CRISPR/Cas9-faciliated knockout of DPYSL2-B in iPSCs followed by Ngn2-induced differentiation to glutamatergic neurons showed a reduction in DPYSL2-B/CRMP2-B RNA and protein with no observable impact on DPYSL2-A/CRMP2-A. The average length of dendrites in knockout neurons was reduced up to 58% compared to controls. Transcriptome analysis revealed disruptions in pathways highly relevant to psychiatric disease including mTOR signaling, cytoskeletal dynamics, immune function, calcium signaling, and cholesterol biosynthesis. We also observed a significant enrichment of the differentially expressed genes in SCZ-associated loci from genome-wide association studies (GWAS). Our findings expand our previous results to neuronal cells, clarify the functions of the human DPYSL2-B isoform and confirm its involvement in molecular pathologies shared between many psychiatric diseases.

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Fig. 1: Generation and characterization of DPYSL2-B frameshift iPSCs.
Fig. 2: Generation and characterization of DPYSL2-B frameshift glutamatergic neurons.
Fig. 3: Transcriptomic analysis of DPYSL2-B frameshift neurons.

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Acknowledgements

We would like to thank Dr. Debamitra Das and Dr. Linglei Jiang for their advice on neuronal differentiation and neuronal protein extraction, respectively. Thank you to Dr. Arianna Anzmann, Dr. Sarah Poll and Olivia Sniezek for their guidance on Western blotting, and Cassandra Obie for tissue culture support. Thank you to Lindsay Young for assisting with off-target analysis and Marah Wahbeh for troubleshooting support. We would also like to thank Dr. Vasiliki Machairaki and her lab for their help with immunocytochemistry and fluorescence microscopy. This project was funded by National Institute of Mental Health grants P50 MH094268, R01 MH113215 and RF1 MH122936 to DA. Figures were created with BioRender.com.

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  1. Predoctoral Training Program in Human Genetics, McKusick-Nathans Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Kyra L. Feuer

  2. McKusick-Nathans Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Kyra L. Feuer, Xi Peng, Christian K. Yovo & Dimitrios Avramopoulos

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KLF performed all the laboratory work, performed bioinformatics analysis, and contributed significantly to writing and editing the manuscript. XP performed RNA sequencing data analysis and differential expression analysis and proofreading of the manuscript. CKY provided support for all laboratory aspects of the project (reagent orders and preparation, support with tissue cultures) and proofreading of the manuscript. DA conceptualized and designed the project, supervised and interpreted experiments, contributed to writing and editing the manuscript and secured the necessary funding.

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Correspondence to Dimitrios Avramopoulos.

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Feuer, K.L., Peng, X., Yovo, C.K. et al. DPYSL2/CRMP2 isoform B knockout in human iPSC-derived glutamatergic neurons confirms its role in mTOR signaling and neurodevelopmental disorders. Mol Psychiatry 28, 4353–4362 (2023). https://doi.org/10.1038/s41380-023-02186-w

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