Formation of the Drosophila salivary gland

描述（由申请方提供）：在发育过程中，通过局部转录因子和信号事件的组合指定器官前体。细胞生长、重排和定向迁移在器官发育过程中塑造和定位器官。最终，不同器官内的细胞获得独特的生理适应，使它们能够执行其专门的功能。许多在特定器官发育过程中起作用的分子途径也需要在成人结构中维持功能。不能实现和维持专门功能往往会导致器官衰竭和退化，因此与几种人类疾病和出生缺陷有关。为了了解器官如何形成并获得其独特的生理适应性，我们正在使用一个简单的模型：果蝇唾液腺，这是动物中最大的分泌器官。它由两个成对的分泌管和较小的导管组成，分泌管合成和分泌大量蛋白质，较小的导管将分泌管连接到口腔并作为唾液腺分泌物的管道。在以前的工作中，我们和其他人已经确定了本地化的转录因子和信号转导通路，这些转录因子和信号转导通路决定了唾液腺的形成位置，控制了招募到唾液腺的细胞数量，并区分了该器官中的主要细胞类型。我们还确定了六个早期表达的转录因子，对唾液腺的形态和生理有深远的影响。在本申请中，我们建议（1）确定在早期唾液腺中表达的六种转录因子基因的下游靶点，这些基因是腺体形态发生和生理学的关键;（2）确定细胞形状变化和细胞重排对管形成的相对贡献;以及（3）确定周围组织如何有助于唾液腺的最终正确放置。在目标1中，我们将使用整体原位杂交来确定193+已知的唾液腺基因中的哪一个受六个转录因子基因中的每一个的调控。在目标2中，我们将使用标记细胞的实时成像来确定在管内陷和伸长期间通常发生多少细胞重排，并且我们将表征介导细胞形状变化和重排的基因的转录靶点的关键子集。在目标3中，我们将描述唾液腺导航到正确的最终位置所需的信号通路。

DESCRIPTION (provided by applicant): During development, organ precursors are specified through a combination of localized transcription factors and signaling events. Cell growth, rearrangement and directed migration shape and position organs as they develop. Ultimately, cells within different organs acquire unique physiological adaptations that allow them to perform their specialized functions. Many of the molecular pathways that function during the development of specific organs are also required to maintain function in the adult structures. Failure to achieve and maintain specialized functions often leads to organ failure and degeneration, and is thus linked to several human diseases and birth defects. To learn how organs form and acquire their unique physiological adaptations, we are using a simple model: the Drosophila salivary gland, which is the largest secretory organ in the animal. It is comprised of two paired secretory tubes, which synthesize and secrete large amounts of proteins, and smaller duct tubes, which connect the secretory tubes to the mouth and serve as a conduit for the salivary gland secretions. In previous work, we and others have identified the localized transcription factors and signaling pathways that determine where the salivary gland will form, that control the number of cells recruited to a salivary gland fate and that distinguish among the major cell types in this organ. We have also identified six early expressed transcription factors that have profound effects on salivary gland morphology and physiology. In this application, we propose to (1) identify the downstream targets of the six transcription factor genes that are expressed in the early salivary gland and are key to gland morphogenesis and physiology; (2) to determine the relative contributions of cell shape change and cell rearrangement to tube formation; and (3) determine how surrounding tissues contribute to the final correct placement of the salivary gland. In aim 1, we will use whole mount in situ hybridization to determine which of 193+ known salivary gland genes are regulated by each of the six transcription factor genes. In aim 2, we will use live imaging of marked cells to determine how much cell rearrangement normally occurs during tube invagination and elongation, and we will characterize a key subset of the transcriptional targets of the genes that mediate cell shape change and rearrangement. In aim 3, we will characterize signaling pathways necessary for the salivary gland to navigate to its correct final position.