Disrupted-in-schizophrenia 1-mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling

Shih Yu Chen, Pei Hsin Huang, Hwai-Jong Cheng

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50 Scopus citations


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 wellcharacterized 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 TRIORAC- PAK signaling pathway can be exploited and modulated by DISC1 to regulate axonal connectivity in the developing brain.

Original languageEnglish (US)
Pages (from-to)5861-5866
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number14
StatePublished - Apr 5 2011


  • Genetic model
  • Rolipram

ASJC Scopus subject areas

  • General


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