Choanoflagellate colony formation as a simple model for animal multicellularity

描述（由申请人提供）：细胞粘附和信号机制的进化对动物多细胞的起源至关重要。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中合作与竞争的进化冲突。因此，现代动物的发育和生理（包括人类）依赖于由古老的粘附和信号机制形成的调控基础。癌症生物学可能是最突出的例子，说明当基本的调节机制受到损害时，细胞合作与竞争之间的古老紧张关系如何重新出现。通过研究动物最接近的单细胞和集落形成亲属——鞭虫，我们的目标是确定动物多细胞的最小分子工具包。短单胞单鞭毛虫（Monosiga brevicollis）和原海绵毛虫（Proterospongia）的全基因组和EST序列显示，短单鞭毛虫表达动物细胞信号传导和粘附所需的同源基因（如受体酪氨酸激酶和钙粘蛋白）。此外，原海绵体发育高度组织化的菌落，其中邻近细胞通过细胞质桥连接，我们假设这介导了细胞间信号传导和粘附。利用我的实验室产生的鞭虫特异性分子、基因组和细胞生物学资源，我们研究鞭虫集落形成作为动物多细胞进化和发展的简单模型。我们提出三个目标，以确定细胞间相互作用的机制，在原海绵体菌落。首先，我们将描述细胞质桥的发育和超微结构，并测量它们作为信号分子的细胞间通道的能力。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、粘附和中体蛋白的鞭毛同源物的定位和功能。通过结合细胞生物学、功能基因组学和生物化学方法来研究原海绵症的细胞间相互作用，这项研究将为动物发育和癌症的分子基础提供新的见解。

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.