Disrupted-in-Schizophrenia 1–mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling
Open accessAbstract
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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Axonal guidance and reelin signaling are important pathways for nervous system development and have been implicated in neuropsychiatric disorders such as bipolar, SCZ, and ADHD.
“Axonal guidance and reelin signaling are important pathways for nervous system development and have been implicated in neuropsychiatric disorders such as bipolar, SCZ, and ADHD [64–68]”
From An integrated analysis of genes and functional pathways for aggression in human and rodent models (2019) · cites this paper as [67]
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- Authors
- Chen, S.-Y., Huang, P.-H., & Cheng, H.-J.
- Affiliations
- University of California, Davis (US)
- National Taiwan University (TW)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-03-21
- Volume
- 108
- Issue
- 14
- Pages
- 5861-5866
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3078365
- OpenAlex
- W2061378547
- Cited by
- 73
- References
- 46
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 6 · 2022: 4 · 2021: 4 · 2020: 7 · 2019: 6 · 2018: 8 · 2017: 3 · 2016: 3 · 2015: 5 · 2014: 6 · 2013: 4 · 2012: 10
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Taiwan University Hospital
- National Taiwan University
- University of California, Davis
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- disrupted-in-schizophrenia 1, DISC1, axon guidance, Rac1, trios, guanine nucleotide exchange factor, spectrin repeats, growth cones, motor neurons, Caenorhabditis elegans, neuronal connectivity, schizophrenia, brain development, genetic interactions
- MeSH terms
- Animals, Axons, Cell Movement, Chlorocebus aethiops, Humans, Mice, Transgenic, Nerve Tissue Proteins, Phosphoproteins, Blotting, Western, Signal Transduction, Mutagenesis, Site-Directed, Caenorhabditis elegans, Protein Serine-Threonine Kinases, DNA Primers, Microscopy, Confocal, COS Cells, GTP Phosphohydrolases, Guanine Nucleotide Exchange Factors, rac1 GTP-Binding Protein, RNA Interference, Immunoprecipitation, Mice, p21-Activated Kinases
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