Regulation of TCF4 transcriptional activity in neurons

PI: Tonis Timmusk

Institution: Tallinn University of Technology

MDBR Statistics

Institutions Awarded


Countries Awarded


# of Awards


Total Amount


Transcription factor TCF4 (alias ITF2, SEF2 or E2-2) is a broadly expressed protein involved in the development and functioning of many different cell types. Recent studies point to important roles for TCF4 in the nervous system. Specifically, human TCF4 gene is implicated in susceptibility to schizophrenia and mutations in TCF4 cause Pitt-Hopkins syndrome (PTHS), a rare developmental disorder characterized by severe motor and mental retardation, typical facial features and breathing anomalies. The mutation may be in different parts of the gene, but it appears in only one allele. Whereas in many other genes the other, unaffected allele would be able to compensate for the defect, this is not the case in TCF4. This indicates that the protein encoded by the TCF4 gene is essential for the development of the nervous system, and that human development depends significantly on the amount of this protein in the brain and body.

Our previous data have suggested that synaptic activation of nerve cells, that is the basis of brain function, leads to activation and phosphorylation of TCF4 protein. Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation turns many proteins on and off, thereby altering their function and activity. The current project is aimed to find out how the activity and phosphorylation of TCF4 protein is regulated inside nerve cells of the brain, and to characterize the phosphorylation pattern of activated TCF4. Additionally, we want to determine which genes are targeted by TCF4 in nerve cells after synaptic activation.

Since Pitt-Hopkins syndrome manifests itself at an early stage, there are better chances for its treatment due to the greater plasticity of children’s brains. Increasing the amount and/or activity of the functional TCF4 protein produced from the healthy allele is among possible approaches to develop drugs for Pitt-Hopkins syndrome treatment. We believe that our project could lead to the discovery of novel possibilities for increasing the activity of TCF4 in nerve cells that could be useful to develop treatments for therapeutic intervention of Pitt-Hopkins syndrome.