ZFIN ID: ZDB-PUB-111122-37
Common DISC1 Polymorphisms Disrupt Wnt/GSK3β Signaling and Brain Development
Singh, K.K., De Rienzo, G., Drane, L., Mao, Y., Flood, Z., Madison, J., Ferreira, M., Bergen, S., King, C., Sklar, P., Sive, H., and Tsai, L.H.
Date: 2011
Source: Neuron   72(4): 545-558 (Journal)
Registered Authors: De Rienzo, Gianluca, Sive, Hazel
Keywords: none
MeSH Terms:
  • Animals
  • Brain/growth & development*
  • Brain Chemistry/genetics*
  • Cell Line, Tumor
  • Female
  • Genetic Variation/genetics
  • Glycogen Synthase Kinase 3/genetics*
  • HEK293 Cells
  • Humans
  • Mice
  • Nerve Tissue Proteins/genetics*
  • Phenotype
  • Polymorphism, Genetic/genetics*
  • Pregnancy
  • Signal Transduction/genetics*
  • Wnt3A Protein/genetics*
  • Zebrafish
PubMed: 22099458 Full text @ Neuron
FIGURES
ABSTRACT
Disrupted in Schizophrenia-1 (DISC1) is a candidate gene for psychiatric disorders and has many roles during brain development. Common DISC1 polymorphisms (variants) are associated with neuropsychiatric phenotypes including altered cognition, brain structure, and function; however, it is unknown how this occurs. Here, we demonstrate using mouse, zebrafish, and human model systems that DISC1 variants are loss of function in Wnt/GSK3β signaling and disrupt brain development. The DISC1 variants A83V, R264Q, and L607F, but not S704C, do not activate Wnt signaling compared with wild-type DISC1 resulting in decreased neural progenitor proliferation. In zebrafish, R264Q and L607F could not rescue DISC1 knockdown-mediated aberrant brain development. Furthermore, human lymphoblast cell lines endogenously expressing R264Q displayed impaired Wnt signaling. Interestingly, S704C inhibited the migration of neurons in the developing neocortex. Our data demonstrate DISC1 variants impair Wnt signaling and brain development and elucidate a possible mechanism for their role in neuropsychiatric phenotypes.
ADDITIONAL INFORMATION