ArticleProceedings of the National Academy of Sciences of the United States of America2011
Disrupted-in-Schizophrenia 1-mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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45 citing papers in PubMed, 70 citations in OpenAlex.
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- The organization of frontostriatal brain wiring in non-affective early psychosis compared with healthy subjects using a novel diffusion imaging fiber cluster analysis.Molecular psychiatry · 2023Article
- Pathogenic TRIO variants associated with neurodevelopmental disorders perturb the molecular regulation of TRIO and axon pathfinding in vivo.Molecular psychiatry · 2023Article
- Interneuron odyssey: molecular mechanisms of tangential migration.Frontiers in neural circuits · 2023Review
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- The p21-activated kinases in neural cytoskeletal remodeling and related neurological disorders.Protein & cell · 2022Review
- Identification of novel immune-related targets mediating disease progression in acute pancreatitis.Frontiers in cellular and infection microbiology · 2022Article
- Analysis of Molecular Networks in the Cerebellum in Chronic Schizophrenia: Modulation by Early Postnatal Life Stressors in Murine Models.International journal of molecular sciences · 2021Article
- Wnt signaling establishes the microtubule polarity in neurons through regulation of Kinesin-13.The Journal of cell biology · 2021Article
- Functional brain defects in a mouse model of a chromosomal t(1;11) translocation that disrupts DISC1 and confers increased risk of psychiatric illness.Translational psychiatry · 2021Article
- Trio family proteins as regulators of cell migration and morphogenesis in development and disease - mechanisms and cellular contexts.Journal of cell science · 2021Review
- Novel loss-of-function variants in TRIO are associated with neurodevelopmental disorder: case report.BMC medical genetics · 2020Article
- Bioinformatic analysis of the potential molecular mechanism of PAK7 expression in glioblastoma.Molecular medicine reports · 2020Article
- Kalirin and Trio: RhoGEFs in Synaptic Transmission, Plasticity, and Complex Brain Disorders.Trends in neurosciences · 2020Review
- Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders.American journal of human genetics · 2020Article
- NCBP2 modulates neurodevelopmental defects of the 3q29 deletion in Drosophila and Xenopus laevis models.PLoS genetics · 2020Article
- Stress-Sensitive Protein Rac1 and Its Involvement in Neurodevelopmental Disorders.Neural plasticity · 2020Review
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Defects in neuronal connectivity of the brain are well documented among schizophrenia patients. Although the schizophrenia susceptibility gene Disrupted-in-Schizophrenia 1 (DISC1) has been implicated in various neurodevelopmental processes, its role in regulating axonal connections remains elusive. Here, a heterologous DISC1 transgenic system in the relatively simple and well-characterized Caenorhabditis elegans motor neurons has been established to investigate whether DISC1 regulates axon guidance during development. Transgenic DISC1 in C. elegans motor neurons is enriched in the migrating growth cones and causes guidance defects of their growing axons. The abnormal axonal phenotypes induced by DISC1 are similar to those by gain-of-function rac genes. In vivo genetic interaction studies revealed that the UNC-73/TRIO-RAC-PAK signaling pathway is activated by ectopic DISC1 in C. elegans motor axons. Using in vitro GST pull-down and coimmunoprecipitation assays, we found that DISC1 binds specifically to the amino half of spectrin repeats of TRIO, thereby preventing TRIO's amino half of spectrin repeats from interacting with its first guanine nucleotide exchange factor (GEF) domain, GEF1, and facilitating the recruitment of RAC1 to TRIO. In cultured mammalian cells, RAC1 is activated by increased TRIO's GEF activity when DISC1 is present. These results together indicate that the TRIO-RAC-PAK signaling pathway can be exploited and modulated by DISC1 to regulate axonal connectivity in the developing brain.
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