Division of Biomedical Sciences, University of California, Riverside, Riverside, CA, USA.
Division of Biomedical Sciences, University of California, Riverside, Riverside, CA, USA.
Stem Cell Reports. 2023 Nov 14;18(11):2254-2267. doi: 10.1016/j.stemcr.2023.10.002. Epub 2023 Oct 26.
Mowat-Wilson syndrome is caused by mutations in ZEB2, with patients exhibiting characteristics indicative of neural crest (NC) defects. We examined the contribution of ZEB2 to human NC formation using a model based on human embryonic stem cells. We found ZEB2 to be one of the earliest factors expressed in prospective human NC, and knockdown revealed a role for ZEB2 in establishing the NC state while repressing pre-placodal and non-neural ectoderm genes. Examination of ZEB2 N-terminal mutant NC cells demonstrates its requirement for the repression of enhancers in the NC gene network and proper NC cell terminal differentiation into osteoblasts and peripheral neurons and neuroglia. This ZEB2 mutation causes early misexpression of BMP signaling ligands, which can be rescued by the attenuation of BMP. Our findings suggest that ZEB2 regulates early human NC specification by modulating proper BMP signaling and further elaborate the molecular defects underlying Mowat-Wilson syndrome.
Mowat-Wilson 综合征是由 ZEB2 突变引起的，患者表现出神经嵴（NC）缺陷的特征。我们使用基于人类胚胎干细胞的模型，研究了 ZEB2 对人类 NC 形成的贡献。我们发现 ZEB2 是最早在拟胚 NC 中表达的因子之一，敲低发现 ZEB2 在建立 NC 状态的同时，抑制前神经嵴和非神经外胚层基因。检查 ZEB2 N 端突变 NC 细胞表明其需要抑制 NC 基因网络中的增强子，并正确分化为成骨细胞和外周神经元和神经胶质。这种 ZEB2 突变导致 BMP 信号配体的早期异常表达，BMP 的衰减可以挽救这种异常表达。我们的研究结果表明，ZEB2 通过调节适当的 BMP 信号来调节早期人类 NC 的特化，并进一步阐述了 Mowat-Wilson 综合征的分子缺陷。
