Formation of the Drosophila salivary gland

描述（由申请人提供）：果蝇唾液腺（SG）是揭示分泌管状器官（如胰腺、乳腺和人类分泌腺）形成和生理特化的分子和细胞事件的理想模型。SG是一种简单的管状器官，它的形成与高等动物更复杂的器官的形态发生变化相同，包括细胞形状、粘附和运动的变化。SG也是胚胎中最大的分泌器官，为细胞如何获得高水平分泌能力以及能力的变化如何与分泌内容的表达协调提供了理想的模型。三个关键的转录因子在SG的特殊分泌细胞中表达，从腺体形成开始到变态的早期阶段，以及在成人SG中。每种转录因子在SG生物发生的不同方面起着重要作用。翅状螺旋DNA结合蛋白叉头（Fkh）是SG存活、形态发生以及维持自身和其他SG特异性转录因子表达所必需的。bZip转录因子CrebA通过提高分泌细胞器和分泌货物蛋白组分的表达来增加分泌能力。bHLH DNA结合蛋白Sage根据其SG有限表达预测可调节组织特异性基因产物的表达。每个转录因子的靶点都是通过微阵列研究和原位杂交发现的。这些调控因子及其目标是揭示形态发生细节和将形态发生与功能专门化联系起来的调控逻辑的绝佳工具集。这一建议的目标是（目的1）表征协调根尖收缩的分子机制，这是许多器官形成所需的细胞形状变化；（目标2）确定与CrebA一起发挥作用的其他关键调节因子，以在专门的分泌器官中实现高水平的分泌能力；（目的3）鉴定组织特异性基因产物，以了解它们的表达如何与形态发生和分泌能力的获得相协调。该研究有望为器官形态发生和生理特化在发育过程中如何耦合提供新的范式。

DESCRIPTION (provided by applicant): The Drosophila salivary gland (SG) is an ideal model for revealing the molecular and cellular events underlying formation and physiological specialization of secretory tubular organs, such as the pancreas, mammary and secretory glands of humans. The SG is a simple tubular organ that forms using the same morphogenetic changes as more complicated organs of higher animals, including changes in cell shape, adhesion and movement. The SG is also the largest secretory organ in the embryo providing an ideal model for how cells achieve high-level secretory capacity and how changes in capacity are coordinated with the expression of secretory content. Three key transcription factors are expressed in the specialized secretory cells of the SG from the onset of gland formation to the early stages of metamorphosis, as well as in the adult SG. Each transcription factor plays major roles in different aspects of SG biogenesis. The winged helix DNA binding protein Fork head (Fkh) is required for SG survival, for morphogenesis and for maintaining expression of itself and other SG-specific transcription factors. The bZip transcription factor CrebA increases secretory capacity by elevating the expression of protein components of secretory organelles and of secreted cargo. The bHLH DNA binding protein Sage is predicted to regulate expression of tissue-specific gene products based on its SG limited expression. Targets of each transcription factor are being discovered by microarray studies and in situ hybridization. These regulators and their targets are an excellent toolset for revealing the details of morphogenesis and the regulatory logic linking morphogenesis to functional specialization. The goals of this proposal are (Aim 1) to characterize the molecular machinery that coordinates apical constriction, a cell shape change required for the formation of many organs; (Aim 2) to identify other key regulators that function with CrebA to achieve high-level secretory capacity in specialized secretory organs; (Aim 3) to identify tissue- specific gene products to learn how their expression is coordinated with morphogenesis and acquisition of secretory capacity. This study is expected to provide new paradigms for how organ morphogenesis and physiological specialization are coupled during development. PUBLIC HEALTH RELEVANCE: The salivary glands form by the same cell shape changes that form the neural tube of humans. Knowing how changes in cell shape are controlled will lead to better prenatal practices for the prevention of spina bifida and other neural tube defects. Also, since many human diseases are related to secretory dysfunction, learning how cells normally acquire high-level secretory capacity should reveal better treatments.