The DPYSL2 gene connects mTOR and schizophrenia

Abstract

We previously reported a schizophrenia-associated polymorphic CT di-nucleotide repeat (DNR) at the 5′-untranslated repeat (UTR) of DPYSL2, which responds to mammalian target of Rapamycin (mTOR) signaling with allelic differences in reporter assays. Now using microarray analysis, we show that the DNR alleles interact differentially with specific proteins, including the mTOR-related protein HuD/ELAVL4. We confirm the differential binding to HuD and other known mTOR effectors by electrophoretic mobility shift assays. We edit HEK293 cells by CRISPR/Cas9 to carry the schizophrenia risk variant (13DNR) and observe a significant reduction of the corresponding CRMP2 isoform. These edited cells confirm the response to mTOR inhibitors and show a twofold shortening of the cellular projections. Transcriptome analysis of these modified cells by RNA-seq shows changes in 12.7% of expressed transcripts at a false discovery rate of 0.05. These transcripts are enriched in immunity-related genes, overlap significantly with those modified by the schizophrenia-associated gene, ZNF804A, and have a reverse expression signature from that seen with antipsychotic drugs. Our results support the functional importance of the DPYSL2 DNR and a role for mTOR signaling in schizophrenia.

Recent Advances in the Genetics of Schizophrenia

“…Chen et al[103] studied the ZNF804A gene by analyzing the effects of a gene knockdown in neurons derived from human induced pluripotent stem cells and reported enrichment of downregulated genes involved in interferon signaling. Pham et al [139], following up on their own linkage, association, and functional data [140-142], modified an isoform-specific promoter of the DPYSL2 gene by CRISPR/Cas9 and found a complementary effect to transcriptomic changes induced by antipsychotics, enrichment in immune system process genes, as well as a significant overlap with the results of Chen et al [103]. This last point is of interest as it connects ZNF804A and DPYSL2 , two genes that have no other known functional connection other than their associations with schizophrenia.…”

“…The applications one can imagine are only limited by what is ethical to do in a lab. The small effect sizes may still be a problem, but others and we have shown that when one works with modified or edited cells, small effect variants can lead to robust cellular phenotypes [103, 105, 139, 176]. These technologies are new, and there is still much space for improvement, including editing efficiency [177], uniform and specific differentiation [178, 179], the time needed for maturation, and the faithful recapitulation of cortical circuits by organoids [180].…”

Different Modulation of Rps6 Phosphorylation by Risperidone in Striatal Cells Sub Populations: Involvement of the mTOR Pathway in Antipsychotic-Induced Extrapyramidal Symptoms in Mice

“…Recently, various authors have implicated the mTOR signaling pathway in the modulation exerted by AP drugs such as thioridazine [12,13], olanzapine [14], haloperidol [15,16] and risperidone [17], among others. In parallel, several studies provide evidence for the involvement of disrupted mTOR signaling in the neuropathology of schizophrenia [18].…”

Integrative network analysis reveals biological pathways associated with Williams syndrome

“…Of particular note is the identification of ASD candidate genes ( CYFIP1 and DPYSL2 ) as hub genes in the M4 module (Figure H). CYFIP1 is involved in cytoskeletal remodeling in neurons (Oguro‐Ando et al., ), while DPYSL2 is important for axon outgrowth and mTOR signaling‐related processes (Pham et al., ). Furthermore, the M22 module, which included genes within the 7q11.23 region, was enriched in factors related to the regulation of fibroblasts migration and insulin signaling pathway (Figure E,F).…”