Molecular and Cellular Function of Transcription Factor 4 in Pitt-Hopkins Syndrome

Abstract

Transcription factor 4 (TCF4, also known as ITF2 or E2-2) is a type I basic helix-loop-helix transcription factor. Autosomal dominant mutations in TCF4 cause Pitt-Hopkins syndrome (PTHS), a rare syndromic form of autism spectrum disorder. In this review, we provide an update on the progress regarding our understanding of TCF4 function at the molecular, cellular, physiological, and behavioral levels with a focus on phenotypes and therapeutic interventions. We examine upstream and downstream regulatory networks associated with TCF4 and discuss a range of in vitro and in vivo data with the aim of understanding emerging TCF4-specific mechanisms relevant for disease pathophysiology. In conclusion, we provide comments about exciting future avenues of research that may provide insights into potential new therapeutic targets for PTHS.

Keywords: Basic helix-loop-helix; Neurodevelopmental disorder; Oligodendrocyte; Pitt-Hopkins syndrome; Transcription factor 4.

Fig. 1.. Disease causing mutations in Tcf4 disrupt brain development at various developmental stages and ultimately compromise behavior.

TCF4 is expressed in radial glia cells (RG), progenitor cells, excitatory neurons, inhibitory neurons, astrocytes, oligodendrocyte precursor cells (OPC), and oligodendrocytes (OLs). In the neuronal lineage, Tcf4 mutation disrupts progenitor proliferation and fate specification, migration, differentiation, maturation, morphology, excitability, and plasticity. In the oligodendrocyte lineage, Tcf4 mutation enhances OPC proliferation and reduces the density of mature OLs. TCF4 is expressed in astrocytes and interneurons, but how Tcf4 mutation in these cell types affects their function is unknown. Ultimately, these developmental phenotypes lead to behavioral deficits in PTHS mouse models. Bold type indicates biological process for which Tcf4 mutation produces a phenotype. iOL = immature oligodendrocyte, mOL = mature oligodendrocyte.