TCF4 in human OPC differentiation

Heterozygous mutations of TCF4 in humans cause Pitt-Hopkins-Syndrome, a neurodevelopmental disease associated with intellectual disability and brain malformations. While most studies focus on the role of TCF4 in neural stem cells and neurons, we here set out to assess the implication of TCF4 for oligodendroglial differentiation. We discovered that both, monoallelic as well as biallelic mutations in TCF4 result in a diminished capacity to differentiate human neural progenitor cells towards myelinating oligodendrocytes through forced expression of the transcription factors SOX10, OLIG2, and NKX6.2. Using this experimental strategy, we established a novel organoid model, which generates oligodendroglial cells within a human neurogenic tissue-like context. Also here we found a reduced ability of TCF4 heterozygous cells to differentiate towards oligodendroglial cells. In sum, we establish a role for human TCF4 in oligodendrocyte differentiation and provide a model system, which allows to dissect the disease etiology in a human tissue-like context.