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, the researchers derive neural progenitor cells, neurons, and brain organoids from skin fibroblasts obtained from children with Pitt-Hopkins Syndrome, an autism spectrum disorder, carrying clinically relevant mutations in TCF4. They show that neural progenitors bearing these mutations have reduced proliferation and impaired capacity to differentiate into neurons and identify a potentially clinically relevant mechanism. Moreover, they 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 signalling. This work delineates pathological mechanisms in neural cells harbouring TCF4 mutations and provides a potential target for therapeutic strategies for genetic disorders associated with this gene.
Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content
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