TCF7L2, encoding a transcription factor of the LEF/TCF family that actuates the canonical WNT signaling pathway, is best known for its extraordinarily high levels of association with type 2 diabetes (T2D) and related metabolic disorders in the human population. However, TCF7L2 is also associated with autism spectrum disorder, schizophrenia, and addictive behaviors in humans, and specific brain pathologies together with abnormal behaviors in mice. Fitting with these phenotypes, emerging evidence places the TCF7L2 protein at the center of regulatory networks controlling the differentiation of diverse neuron populations across the developing brain. 

PNRI’s Stubbs Lab first became interested in TCF7L2 because their research showed that WNT activation is a deeply conserved feature of stress response in animals, and the TCF7L2 is the WNT activator that is most consistently up regulated by social stress in mice. PNRI’s research is focused on this WNT activator’s role in regulating the development of stress-responsive neurons across the brain. 

This research team is particularly focused on the role of TCF7L2 may play in a conserved network that controls brain development but are also interested in the susceptibility to the devastating stress-induced metabolic disorders that are so prevalent in human patients. The Stubbs Lab is working to expand the stress response network, including additional, interacting factors and genetic modifiers in human patient populations with mathematical methods developed by our collaborator and PNRI colleague, Dr. David Galas.