Molecular control of tissue morphogenesis

描述（由申请人提供）：发育生物学的一个主要挑战是了解如何在细胞和分子水平上产生组织结构的大规模变化。二十年的分子遗传学研究为控制细胞命运和模式的机制提供了见解，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尚未得到很好的理解。脊椎动物和无脊椎动物的组织结构的一个保守特征是从头部到尾部延长的体轴。极化细胞重排在塑造几种生物体的体轴中起着重要作用。上皮组织中的细胞重排受到细胞间粘附连接网络的限制，其连续性在整个延伸过程中得以保持。因此，上皮细胞可以利用组织伸长的独特策略，这些上皮细胞必须动态重塑细胞粘附而不损害上皮完整性。最近的工作提供了深入了解的物理机制，轴伸长过程中的力的产生和细胞粘附的力学基础。特别是，轴伸长所需的许多蛋白质，包括收缩机制和细胞-细胞连接的组分，不对称地定位在组织平面中。这种不对称的本地化似乎是至关重要的平面极化力的产生和交界处的轴伸长过程中重塑。然而，上游信号，产生空间调节肌动球蛋白收缩性和粘附对齐细胞重排与全球组织轴还没有很好地理解。我们已经表明，Rho-激酶和Abl酪氨酸激酶是不对称的本地化和控制轴伸长过程中的收缩力和细胞粘附动力学的分布。我们假设这些激酶响应上游空间线索，产生空间调节的收缩性和粘附性，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上游的空间机制，调节这两个保守的蛋白激酶的定位和活动是必不可少的轴伸长。此外，我们将使用计算方法和荧光蛋白成像研究的动态机制，平面极性的建立和重塑整个延伸。连接重塑对于发育期间的上皮形态发生是重要的，并且成人中上皮维持和修复的缺陷与诸如囊性肾病和肿瘤细胞转移的疾病相关。更好地理解调节上皮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失调如何导致人类疾病的见解。

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.