Abstract:
Cell fate determination is a necessary and tightly regulated process for producing different cell types and structures during development. Cranial neural crest cells (CNCCs) are unique to vertebrate embryos and emerge from the neural plate borders into multiple cell lineages that differentiate into bone, cartilage, neurons and glial cells. We have previously reported that Irf6 genetically interacts with Twist1 during CNCC-derived tissue formation. Here, we have investigated the mechanistic role of Twist1 and Irf6 at early stages of craniofacial development. Our data indicate that TWIST1 is expressed in endocytic vesicles at the apical surface and interacts with β/δ-catenins during neural tube closure, and Irf6 is involved in defining neural fold borders by restricting AP2α expression. Twist1 suppresses Irf6 and other epithelial genes in CNCCs during the epithelial-to-mesenchymal transition (EMT) process and cell migration. Conversely, a loss of Twist1 leads to a sustained expression of epithelial and cell adhesion markers in migratory CNCCs. Disruption of TWIST1 phosphorylation in vivo leads to epidermal blebbing, edema, neural tube defects and CNCC-derived structural abnormalities. Altogether, this study describes a previously uncharacterized function of mammalian Twist1 and Irf6 in the neural tube and CNCCs, and provides new target genes for Twist1 that are involved in cytoskeletal remodeling.
摘要:
细胞命运决定是在发育过程中产生不同细胞类型和结构的必要且严格调节的过程。颅骨神经c细胞(CNCC)是脊椎动物胚胎所特有的,并从神经板边界出现为分化为骨骼的多个细胞谱系,软骨,神经元和神经胶质细胞。我们以前报道过Irf6在CNCC来源的组织形成过程中与Twist1发生遗传相互作用。这里,我们研究了Twist1和Irf6在颅面发育早期的机制作用.我们的数据表明,TWIST1在顶端表面的内吞囊泡中表达,并在神经管闭合期间与β/δ-catenins相互作用,和Irf6通过限制AP2α表达参与定义神经折叠边界。Twist1在上皮间质转化(EMT)过程和细胞迁移期间抑制CNCC中的Irf6和其他上皮基因。相反,Twist1的缺失导致迁移CNCC中上皮细胞和细胞粘附标志物的持续表达。体内TWIST1磷酸化的破坏导致表皮起泡,水肿,神经管缺陷和CNCC衍生的结构异常。总之,这项研究描述了哺乳动物Twist1和Irf6在神经管和CNCC中的先前未表征的功能,并为Twist1提供了参与细胞骨架重塑的新靶基因。