Papes F, Camargo AP, de Souza JS, Carvalho VMA, Szeto RA, LaMontagne E, Teixeira JR, Avansini SH, Sánchez-Sánchez SM, Nakahara TS, Santo CN, Wu W, Yao H, Araújo BMP, Velho PENF, Haddad GG, and Muotri AR.
Nature Communications, 2022.
Scientists use Axion’s bioelectronic assays and other methods to explore neurodevelopment and therapeutic targets in a rare form of autism spectrum disorder.
Transcription Factor 4 (TCF4) has been associated with neurodevelopmental and neuropsychiatric disorders, but scientists do not fully understand the effects of pathological TCF4 mutations on human neural tissue. In this study, researchers use a multiplatform approach to investigate the pathological mechanisms of TCF4 and explore potential therapeutic approaches using neural progenitor cells, neurons, and brain cortical organoids generated from skin fibroblasts obtained from children with Pitt-Hopkins syndrome—a rare autism spectrum disorder caused by mutations in the TCF4 gene and characterized by developmental delay, intellectual impairment, distinctive facial features, breathing difficulties, and seizures.
To explore in vitro neuronal function in the 2D cultures and 3D organoids, the scientists used Axion’s label-free Maestro multielectrode array (MEA) platform and other methods. The findings demonstrated reduced proliferation and neuronal differentiation, resulting in smaller organoid size compared to healthy controls and impaired electrical activity. Importantly, this functional phenotype was rescued by correction of TCF4 expression using CRISPR-based trans-epigenetic manipulation or by pharmacological modulation of Wnt signaling. The authors conclude that these findings may inform future research into the mechanisms of TCF4 mutations and lead to new therapeutic strategies for Pitt-Hopkins syndrome and related genetic disorders.