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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. Overall design: iPS cells from a healthy donor were edited to knock out one DPYSL2 transcript and 6 edited and 6 unedited clones differentiated to excitatory neurons. RNA was extracted and subjected to RNA sequencing, after which the transcriptomes of edited and unedited cells were compared. Details in our publication Mol Psychiatry. 2023 Oct 28(10):4353-4362. doi: 10.1038/s41380-023-02186-w. Epub 2023 Jul 21. PMID: 37479784"],"repository":["ENA"],"description_synonyms":["TOAD-64, 2610315D21Rik, human being, Disorders, Neurodevelopmental Disorder, FKBP12-rapamycin complex-associated protein, CG5092, Nerve, Splice Variants, l(2)k03905, Protein Splice, l(2)k17004, Child, DmTOR, Disorders Usually Diagnosed in Infancy, Human, Childhood or Adolescence, ULIP2, Homo sapiens, Musunc33, Roles, Variant, Concepts, Ulip2, RAFT1, TOR, Isoforms, iPS cell, Mammalian target of rapamycin, Man, Splice Variant, DmelCG8274, DRP-2, AI851130, Protein Splice Variant, Mental Disorders Diagnosed in Childhood, Man (Taxonomy), Bx34, Protein Splice Variants, flat, tor, Protein Isoform, Tpr, TPR, dtor, Disorder, Role Concepts, Neuron, Mental Disorders, Nerve Cell, Frap1, CT24817, dTOR, dTor, ULIP-2, FK506-binding protein 12-rapamycin complex-associated protein 1, single organism signaling, Mechanistic target of rapamycin, Child Mental Disorder, Child Mental, CRMP-2, Modern, N2A3, FRAP1, FRAP2, mTOR, Isoform, FRAP/TOR, DmelCG5092, Cell, Concept, 2.7.11.1, iPSC, Role Concept, Protein, Role, Neurodevelopmental Disorders Usually Diagnosed in Infancy, RAPT1, Nerve Cells, Child Mental Disorders, DHPRP2, DRP2, Rapamycin and FKBP12 target 1, CT24745, Rapamycin target protein 1, AI327068, FRAP, human, Neurodevelopmental, Neurodevelopmental Disorders., Crmp2, CT16317, signalling process, CG8274, 5092, Modern Man, Cells, MTOR, Variants, Mental Disorders Usually Diagnosed in Infancy, neurodevelopmental disorder, CRMP2, humans, Mental Disorder"],"name_synonyms":["TOAD-64, 2610315D21Rik, human being, Disorders, Neurodevelopmental Disorder, FKBP12-rapamycin complex-associated protein, CG5092, Nerve, Splice Variants, l(2)k03905, Protein Splice, l(2)k17004, Child, DmTOR, Disorders Usually Diagnosed in Infancy, Human, Childhood or Adolescence, ULIP2, Homo sapiens, Musunc33, Roles, Variant, Concepts, Ulip2, RAFT1, TOR, Isoforms, iPS cell, Mammalian target of rapamycin, Man, Splice Variant, DmelCG8274, DRP-2, AI851130, Protein Splice Variant, Mental Disorders Diagnosed in Childhood, Man (Taxonomy), Bx34, Protein Splice Variants, flat, tor, Protein Isoform, Tpr, TPR, dtor, Disorder, Role Concepts, Neuron, Mental Disorders, Nerve Cell, Frap1, CT24817, dTOR, dTor, ULIP-2, FK506-binding protein 12-rapamycin complex-associated protein 1, single organism signaling, Mechanistic target of rapamycin, Child Mental Disorder, Child Mental, CRMP-2, Modern, N2A3, FRAP1, FRAP2, mTOR, Isoform, FRAP/TOR, DmelCG5092, Cell, Concept, 2.7.11.1, iPSC, Role Concept, Protein, Role, Neurodevelopmental Disorders Usually Diagnosed in Infancy, RAPT1, Nerve Cells, Child Mental Disorders, DHPRP2, DRP2, Rapamycin and FKBP12 target 1, CT24745, Rapamycin target protein 1, AI327068, FRAP, human, Neurodevelopmental, Neurodevelopmental Disorders., Crmp2, CT16317, signalling process, CG8274, 5092, Modern Man, Cells, MTOR, Variants, Mental Disorders Usually Diagnosed in Infancy, neurodevelopmental disorder, CRMP2, humans, Mental Disorder"],"additional_accession":[]},"is_claimable":false,"name":"DPYSL2/CRMP2 isoform B knockout in human iPSC-derived glutamatergic neurons confirms its role in mTOR signaling and neurodevelopmental disorders","description":"DPYSL2/CRMP2 isoform B knockout in human iPSC-derived glutamatergic neurons confirms its role in mTOR signaling and neurodevelopmental disorders","dates":{"last_updated":"2025-09-24","first_public":"2024-05-31"},"accession":"PRJNA1114671","cross_references":{"GEO":["GSE268103"],"taxon":["9606"],"PubMed":["37479784"]}}