Molecular control of tissue morphogenesis

描述(申请人提供)：发育生物学的一个主要挑战是了解组织结构的大规模变化是如何在细胞和分子水平上产生的。二十年的分子遗传学研究已经为控制细胞命运和图案形成的机制提供了洞察力，但将细胞命运决定转化为细胞和组织形状的形态发生事件还没有被很好地理解。脊椎动物和无脊椎动物组织结构的一个保守特征是体轴从头到尾伸长。极化的细胞重排在塑造几种生物的体轴方面起着重要作用。上皮组织中的细胞重排受到细胞间黏附连接网络的限制，这种网络的连续性在整个伸长过程中保持不变。因此，上皮细胞可以利用独特的组织延长策略，在不损害上皮完整性的情况下，动态地重塑细胞黏附。最近的工作提供了对轴伸长过程中力产生和细胞黏附机制的物理机制的见解。特别是，许多轴伸长所需的蛋白质，包括收缩机械和细胞-细胞连接的组件，不对称地定位在组织的平面上。这种不对称的局部化似乎对平面极化力的产生和轴伸长过程中的连接重塑至关重要。然而，产生空间调节的肌球蛋白收缩和粘附性以使细胞重排与整体组织轴一致的上游信号还没有被很好地理解。我们已经证明，Rho-Kinase和Abl酪氨酸激酶是不对称定位的，并控制着轴伸长过程中收缩力量的分布和细胞黏附动力学。我们假设，这些激酶对上游空间线索做出反应，产生空间调节的收缩和粘连、极化细胞重排和组织伸长。我们将使用分子遗传学、细胞生物学和定量成像的方法来研究调节这两个保守的蛋白激酶的定位和活性的上游空间机制，这两个保守的蛋白激酶是轴伸长所必需的。此外，我们将使用计算方法和荧光蛋白质成像来研究在整个伸长过程中平面极性被建立和重塑的动力学机制。在发育过程中，连接重塑对上皮的形态发生非常重要，成人的上皮维持和修复缺陷与囊性肾脏疾病和肿瘤细胞转移等疾病有关。更好地了解调节上皮细胞伸长的机制可以阐明上皮器官形成的一般原理，并提供对这些过程的错误调节如何导致人类疾病的洞察。

DESCRIPTION (provided by applicant): A major challenge in developmental biology is to understand how large-scale changes in tissue structure are generated on a cellular and molecular level. Two decades of research in molecular genetics have provided insight into the mechanisms that control cell fate and patterning, but the morphogenetic events that translate cell fate determination into the shapes of cells and tissues are not well understood. A conserved feature of tissue architecture in vertebrates and invertebrates is a body axis that is elongated from head to tail. Polarized cell rearrangements play a major role in shaping the body axis of several organisms. Cell rearrangements in epithelial tissues are constrained by a network of adherens junctions between cells whose continuity is maintained throughout elongation. Unique strategies for tissue elongation may therefore be utilized by epithelial cells that must dynamicall remodel cell adhesion without compromising epithelial integrity. Recent work has provided insight into the physical mechanisms that underlie the mechanics of force generation and cell adhesion during axis elongation. In particular, many proteins that are required for axis elongation, including components of the contractile machinery and cell-cell junctions, are asymmetrically localized in the plane of the tissue. This asymmetric localization appears to be crucial for planar polarized force generation and junctional remodeling during axis elongation. However, the upstream signals that generate spatially regulated actomyosin contractility and adhesion to align cell rearrangements with the global tissue axes are not well understood. We have shown that Rho-kinase and Abl tyrosine kinase are asymmetrically localized and control the distribution of contractile forces and cell adhesion dynamics during axis elongation. We hypothesize that these kinases respond to upstream spatial cues to generate spatially regulated contractility and adhesion, polarized cell rearrangement, and tissue elongation. We will use molecular genetic, cell biological, and quantitative imaging approaches to investigate the upstream spatial mechanisms that regulate the localization and activity of these two conserved protein kinases that are essential for axis elongation. In addition, we will use computational methods and fluorescent protein imaging to study the dynamic mechanisms by which planar polarity is established and remodeled throughout elongation. Junctional remodeling is important for epithelial morphogenesis during development, and defects in epithelial maintenance and repair in the adult are associated with diseases such as cystic kidney disease and tumor cell metastasis. A better understanding of the mechanisms that regulate epithelial elongation can elucidate general principles of epithelial organ formation and provide insight into how the misregulation of these processes leads to human disease.