MRC Laboratory of Molecular Biology,Cambridge Biomedical Campus, Cambridge, United Kingdom.
Genetics and Genomic Medicine Programme, Institute of Child Health, University College London, London, United Kingdom.
Elife. 2021 Nov 1;10:e72369. doi: 10.7554/eLife.72369.
During organ development, tubular organs often form from flat epithelial primordia. In the placodes of the forming tubes of the salivary glands in the embryo, we previously identified spatially defined cell behaviors of cell wedging, tilting, and cell intercalation that are key to the initial stages of tube formation. Here, we address what the requirements are that ensure the continuous formation of a narrow symmetrical tube from an initially asymmetrical primordium whilst overall tissue geometry is constantly changing. We are using live-imaging and quantitative methods to compare wild-type placodes and mutants that either show disrupted cell behaviors or an initial symmetrical placode organization, with both resulting in severe impairment of the invagination. We find that early transcriptional patterning of key morphogenetic transcription factors drives the selective activation of downstream morphogenetic modules, such as GPCR signaling that activates apical-medial actomyosin activity to drive cell wedging at the future asymmetrically placed invagination point. Over time, transcription of key factors expands across the rest of the placode and cells switch their behavior from predominantly intercalating to predominantly apically constricting as their position approaches the invagination pit. Misplacement or enlargement of the initial invagination pit leads to early problems in cell behaviors that eventually result in a defective organ shape. Our work illustrates that the dynamic patterning of the expression of transcription factors and downstream morphogenetic effectors ensures positionally fixed areas of cell behavior with regards to the invagination point. This patterning in combination with the asymmetric geometrical setup ensures functional organ formation.
在器官发育过程中，管状器官通常由扁平的上皮原基形成。在胚胎唾液腺形成管的基板中，我们之前鉴定了空间限定的细胞行为，包括细胞楔入、倾斜和细胞插入，这些是管形成初始阶段的关键。在这里，我们研究了确保从最初不对称的原基连续形成狭窄对称管的要求，同时组织整体几何形状不断变化。我们正在使用实时成像和定量方法比较野生型基板和表现出细胞行为中断或初始对称基板组织的突变体，这两种情况都会严重损害基板的内陷。我们发现，关键形态发生转录因子的早期转录模式驱动下游形态发生模块的选择性激活，例如 GPCR 信号通路，它激活顶端-中部肌动球蛋白活性，以驱动未来不对称位置的内陷点的细胞楔入。随着时间的推移，关键因子的转录在基板的其余部分扩展，并且随着细胞位置接近内陷坑，它们的行为从主要的插入转变为主要的顶端收缩。初始内陷点的错位或扩大导致细胞行为早期出现问题，最终导致器官形状缺陷。我们的工作表明，转录因子和下游形态发生效应物表达的动态模式确保了与内陷点相关的固定位置的细胞行为区域。这种模式与不对称的几何结构相结合，确保了功能性器官的形成。
