Dynamics of epithelial morphogenesis

描述：我们建议结合计算和实验方法来研究上皮形态发生的机制，上皮形态发生被定义为将细胞片转化为组织和器官的三维（3d）结构的一系列过程。上皮细胞形态发生的研究对于理解正常发育和阐明发育异常（如神经管缺陷）的起源非常重要。我们将重点关注一种上皮形态发生，它只涉及细胞形状的改变和重排，不依赖于细胞分裂或死亡。这种形态发生的例子包括鱼类心脏发育的早期阶段，鸟类视杯的形成，以及昆虫的中胚层内陷。在我们的实验系统（果蝇的卵子发生）中，一层不分裂的细胞形成了一个精细的三维形状。这种转变是由众所周知的化学信号引起的，这些化学信号指定了一个命运图，即细胞在薄片中的位置与它们在三维结构中的最终位置之间的对应关系。我们的目标是了解二维（2d）命运图是如何转化为三维结构的。回答这个问题对于从简单的后生动物到人类的多种发育系统都很重要。我们的假设是，果蝇卵发生过程中的三维上皮形态发生是由图案细胞片内机械张力的二维分布驱动的。我们将通过计算建模和上皮动力学的实时成像以及通过直接分析图案上皮片的机械张力来验证这一假设。我们的工作将导致一个实验验证的3d上皮形态发生的计算框架。鉴于上皮形态发生过程的高度保守性，我们的研究结果可能会揭示广泛发育系统中的上皮动力学。

DESCRIPTION: We propose to combine computational and experimental approaches to investigate the mechanisms of epithelial morphogenesis, defined as the set of processes that transform sheets of cells into three-dimensional (3d) structures of tissues and organs. Studies of epithelial morphogenesis are important for understanding of normal development and for elucidating the origins of developmental abnormalities, such as neural tube defects. We will focus on a type of epithelial morphogenesis that involves only cell shape changes and rearrangements and does not depend on cell divisions or death. Among the examples of this type of morphogenesis are the early stages of heart development in fish, the formation of optic cups in birds, and mesoderm invagination in insects. In our experimental system (Drosophila oogenesis), a sheet of nondividing cells gives rise to an elaborate 3d shape. This transformation is induced by well-understood chemical signals, which specify a fate map, a correspondence between positions of cells within the sheet and their ultimate positions within the 3d structure. Our goal is to understand how the two-dimensional (2d) fate map is transformed into a 3d structure. Answering this question is important in multiple developmental systems, from simple metazoans to humans. Our hypothesis is that 3d epithelial morphogenesis during Drosophila oogenesis is driven by the 2d distribution of mechanical tensions within the patterned cell sheet. We will test this hypothesis by computational modeling and live imaging of epithelial dynamics and by direct analysis of mechanical tensions in patterned epithelial sheets. Our work will lead to an experimentally validated computational framework for 3d epithelial morphogenesis. Given the highly conserved nature of processes involved in epithelial morphogenesis, the results of or studies may shed light on epithelial dynamics in wide range of developmental systems.