Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content

Transcription Factor 4 (TCF4) has been associated with autism, schizophrenia, and other neuropsychiatric disorders. However, how pathological TCF4 mutations affect the human neural tissue is poorly understood. Here, we derive neural progenitor cells, neurons, and brain organoids from skin fibroblasts obtained from children with Pitt-Hopkins Syndrome carrying clinically relevant mutations in TCF4. We show that neural progenitors bearing these mutations have reduced proliferation and impaired capacity to differentiate into neurons. We identify a mechanism through which TCF4 loss-of-function leads to decreased Wnt signaling and then to diminished expression of SOX genes, culminating in reduced progenitor proliferation in vitro. Moreover, we show reduced cortical neuron content and impaired electrical activity in the patient-derived organoids, phenotypes that were rescued after correction of TCF4 expression or by pharmacological modulation of Wnt signaling. This work delineates pathological mechanisms in neural cells harboring TCF4 mutations and provides a potential target for therapeutic strategies for genetic disorders associated with this gene. Transcription Factor 4 (TCF4) has been associated with autism and schizophrenia. Here, the authors demonstrate aberrant proliferation and differentiation in neural cells and organoids carrying mutations in TCF4.

Automated summary

This study investigates the effect of pathological TCF4 mutations on human neural tissue by deriving neural cells and brain organoids from patients with Pitt-Hopkins Syndrome. The authors demonstrate impaired proliferation and differentiation in neural cells bearing TCF4 mutations and identify the underlying mechanism involving decreased Wnt signaling and reduced expression of SOX genes. They also show reduced cortical neuron content and impaired electrical activity in patient-derived organoids, which could be rescued by correcting TCF4 expression or modulating Wnt signaling pharmacologically.