Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Sao Paulo, 13083-862, Brazil.
Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
Nat Commun. 2022 May 2;13(1):2387. doi: 10.1038/s41467-022-29942-w.
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.
转录因子 4（TCF4）与自闭症、精神分裂症和其他神经精神疾病有关。然而，病理 TCF4 突变如何影响人类神经组织还知之甚少。在这里，我们从患有 Pitt-Hopkins 综合征的儿童的皮肤成纤维细胞中衍生出神经祖细胞、神经元和脑类器官，这些儿童携带有临床相关的 TCF4 突变。我们表明，携带这些突变的神经祖细胞增殖减少，向神经元分化的能力受损。我们确定了一种机制，通过该机制 TCF4 功能丧失导致 Wnt 信号减少，然后导致 SOX 基因表达减少，最终导致体外祖细胞增殖减少。此外，我们还表明，患者来源的类器官中皮质神经元含量减少，电活动受损，而在纠正 TCF4 表达或通过 Wnt 信号转导的药理学调节后，这些表型得到了挽救。这项工作描绘了携带 TCF4 突变的神经细胞中的病理机制，并为与该基因相关的遗传疾病的治疗策略提供了一个潜在的靶点。
