Identification of possible therapeutic targets to rescue neuronal and synaptic dysfunctions caused by deletions and mutations of the TCF20 intellectual disability gene

Among several gene mutations identified as high-risk factors in the pathogenesis of neurodevelopmental disorders, de novo mutations of TCF20 (transcription factor 20) were identified in large-scale exome sequencing data of intellectual disability and autism patients.
An increasing number of patients with TCF20 mutations, including de novo and inherited variants have been recently reported. For these patients, the described clinical features include mild-to-moderate intellectual disability with or without ASD and accompanying features such as proportionate overgrowth and muscular. Recent data suggested that TCF20 plays a major role in neurogenesis because TCF20 knockout mice show neurogenesis defects as well as autistic-like behavioral patterns. Indeed, depletion of TCF20 in neuronal precursors induces a decrease in neuronal differentiation and an increase in neuronal precursors proliferation, which might be responsible for abnormal behaviors.
However the function of TCF20 in neuronal and synapse development and function remains to be clarified. In our laboratory we found that TCF20 is indeed expressed also in the mature brain suggesting that TCF20 might have an important function also in mature neurons. Thus, it’s essential to fully understand the function of TCF20 in the synapse and neuronal circuit formations which alterations are the main molecular pathogenic cause of intellectual disability and ASD. In this project we plan to fully study the function of TCF20 using in vitro, including human induced pluripotent cells derived neurons, and in vivo mouse models. Our project aims to reveal new potential therapeutic targets to treat patients carrying TCF20 deletions/mutations associated with severe intellectual disability and ASD.