Formation of the Drosophila salivary gland

描述（由申请人提供）：果蝇唾液腺（SG）是揭示分泌性管状器官（如人类胰腺、乳腺和分泌腺）形成和生理特化的分子和细胞事件的理想模型。SG是一个简单的管状器官，其形成使用与高等动物的更复杂器官相同的形态发生变化，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，为细胞如何实现高水平的分泌能力以及能力的变化如何与分泌内容物的表达相协调提供了理想的模型。三个关键的转录因子表达在专门的分泌细胞的SG从开始的腺体形成的早期阶段的变态，以及在成年SG。每个转录因子在SG生物发生的不同方面发挥着重要作用。带翼螺旋DNA结合蛋白叉头（Fkh）是SG生存、形态发生以及维持其自身和其他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的蛋白组分的表达来增加分泌能力。预测bHLH DNA结合蛋白Sage基于其SG限制性表达来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。这些监管机构和他们的目标是一个很好的工具集，揭示形态发生的细节和监管逻辑连接形态发生的功能专业化。该建议的目标是（目的1）表征协调顶端收缩的分子机制，顶端收缩是许多器官形成所需的细胞形状变化;（目的2）鉴定与CrebA一起发挥功能以在专门的分泌器官中实现高水平分泌能力的其他关键调节剂;（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协调。这项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。 公共卫生相关性：唾液腺是由形成人类神经管的相同细胞形状变化形成的。了解细胞形状的变化是如何控制的，将有助于更好地预防脊柱裂和其他神经管缺陷的产前实践。此外，由于许多人类疾病与分泌功能障碍有关，了解细胞如何正常获得高水平的分泌能力应该会发现更好的治疗方法。

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.