Choanoflagellate colony formation as a simple model for animal multicellularity

描述(申请人提供)：细胞黏附和信号机制的进化是动物多细胞起源的关键。这些创新促进了多细胞发育和细胞分化，并有助于解决单细胞生物体中合作和竞争之间的进化冲突。因此，现代动物的发育和生理学(包括人类)依赖于古老的黏附和信号机制所形成的调节基础。癌症生物学可能是最突出的例子，说明当基本的调控机制受到损害时，细胞合作与竞争之间的古老紧张关系如何重新出现。通过对脊索鞭毛虫的研究，我们的目标是确定动物多细胞的最小分子工具包。两种脊椎动物Monosiga brevicollis和Proterospongia的全基因组和EST序列表明，脊椎动物表达动物细胞信号和黏附所需的基因(如受体酪氨酸激酶和钙粘附素)的同源基因。此外，原脊椎病形成高度有组织的菌落，在这些菌落中，相邻的细胞通过细胞质桥梁相连，我们假设这些桥梁介导细胞间的信号传递和黏附。利用本实验室产生的特定分子、基因组和细胞生物资源，我们研究了脊椎动物群体的形成，作为动物多细胞进化和发展的一个简单模型。我们提出了三个目标来确定原脊椎病菌落中细胞间相互作用的机制。首先，我们将描述细胞质桥梁的发育和超微结构，并测量它们作为细胞间信号分子管道的能力。其次，我们将使用蛋白质组学和功能基因组学方法来鉴定与细胞质桥形成相关的分子。第三，我们将研究动物信号、黏附和中体蛋白的脊鞭毛虫同源物的定位和功能。通过将细胞生物学、功能基因组和生化方法结合起来研究原脊髓灰质炎的细胞间相互作用，这项研究将为动物发育和癌症的分子基础提供新的见解。 与公共卫生相关：细胞黏附和通讯缺陷导致细胞无法正确协调其行为，并可能导致灾难性的发育缺陷和癌症。动物细胞相互作用的基本机制可能最好在脊椎动物身上进行研究，这是一种新兴的模式生物，包含了动物多细胞的基本分子工具箱。通过重建细胞间相互作用的祖先，这项研究旨在为动物的发育、健康和疾病提供新的见解。

DESCRIPTION (provided by applicant): The evolution of cell adhesion and signaling mechanisms was essential for the origin of animal multicellularity. These innovations facilitated multicellular development and cell differentiation, and helped resolve the evolutionary conflict between cooperation and competition in single celled organisms. Modern animal development and physiology (including in humans) therefore rests upon a regulatory foundation nucleated by ancient adhesion and signaling mechanisms. Cancer biology is perhaps the most prominent example of how ancient tensions between cell cooperation and competition can re-emerge when fundamental regulatory mechanisms are compromised. By studying choanoflagellates, the closest living single-celled and colony-forming relatives of animals, we aim to determine the minimal molecular toolkit for animal multicellularity. Whole genome and EST sequences from two choanoflagellates, Monosiga brevicollis and Proterospongia, reveal that choanoflagellates express homologs of genes required for cell signaling and adhesion in animals (e.g. receptor tyrosine kinases and cadherins). In addition, Proterospongia develops highly organized colonies in which neighboring cells are connected by cytoplasmic bridges that we hypothesize mediate intercellular signaling and adhesion. Using choanoflagellate-specific molecular, genomic, and cell biological resources generated by my lab, we study choanoflagellate colony formation as a simple model for the evolution and development of animal multicellularity. We propose three aims to determine the mechanisms of intercellular interactions in Proterospongia colonies. First, we will characterize the development and ultrastructure of cytoplasmic bridges and measure their ability to act as intercellular conduits for signaling molecules. Second, we will use proteomic and functional genomic approaches to identify molecules associated with the formation of cytoplasmic bridges. Third, we will investigate the localization and function of choanoflagellate homologs of animal signaling, adhesion, and midbody proteins. By uniting cell biology, functional genomic and biochemical approaches in the study of intercellular interactions in Proterospongia, this research will offer new insights into the molecular underpinnings of animal development and cancer. PUBLIC HEALTH RELEVANCE: Defects in cell adhesion and communication result in a failure of cells to coordinate their behavior properly, and can give rise to catastrophic developmental defects and cancer. The fundamental mechanisms by which animal cells interact may best be studied in the choanoflagellate, an emerging model organism that contains the basic molecular toolkit for animal multicellularity. By reconstructing the ancestry of intercellular interactions, this research aims to provide new insights into animal development, health and disease.