Furlanetto Federica, Flegel Nicole, Kremp Marco, Spear Chiara, Fröb Franziska, Alfonsetti Margherita, Bohl Bettina, Krumbiegel Mandy, Turan Sören, Reis Andre, Lie Dieter C, Winkler Jürgen, Falk Sven, Wegner Michael, Karow Marisa
Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Life Sci Alliance. 2025 Mar 28;8(6). doi: 10.26508/lsa.202403102. Print 2025 Jun.
Heterozygous mutations of in humans cause Pitt-Hopkins syndrome, a neurodevelopmental disease associated with intellectual disability and brain malformations. Although 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 and biallelic mutations in result in a diminished capacity to differentiate human neural progenitor cells toward myelinating oligodendrocytes through the 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 toward oligodendroglial cells. In sum, we establish a role of human TCF4 in oligodendrocyte differentiation and provide a model system, which allows to dissect the disease etiology in a human tissue-like context.
人类中TCF4的杂合突变会导致皮特-霍普金斯综合征，这是一种与智力残疾和脑畸形相关的神经发育疾病。尽管大多数研究聚焦于TCF4在神经干细胞和神经元中的作用，但我们在此着手评估TCF4对少突胶质细胞分化的影响。我们发现，通过强制表达转录因子SOX10、OLIG2和NKX6.2，TCF4的单等位基因和双等位基因突变都会导致人类神经祖细胞向有髓鞘形成的少突胶质细胞分化的能力减弱。利用这一实验策略，我们建立了一种新型类器官模型，该模型可在类似人类神经发生组织的环境中产生少突胶质细胞。此外，我们在此发现TCF4杂合细胞向少突胶质细胞分化的能力降低。总之，我们确立了人类TCF4在少突胶质细胞分化中的作用，并提供了一个模型系统，该系统能够在类似人类组织的环境中剖析疾病病因。
