Control of developmental timing and body size in Drosophila

描述（由申请人提供）：所有多细胞生物体的正确发育不仅需要细胞相互作用的正确空间控制，还需要发育期间特定基因表达程序的正确时机。改变许多发育过程的时间可以显着影响动物最终的身体大小，生殖能力和衰老。在昆虫中，发育转变（即蜕皮和变态）的时间由20-羟基蜕皮激素（20 E）介导，20 E是一种小的循环亲脂性类固醇激素，其结合并激活核受体超家族的转录因子。虽然控制对20 E的反应的遗传层次结构受到了相当大的关注，但目前对控制激素产生及其释放的时间的机制知之甚少。在这个建议中，我们将确定如何prothoraciotropic激素，从神经元释放的肽，支配前胸腺（PG）控制激素的生产和释放。在目标1中，我们将确定PG细胞何时接收PTTH信号以及是什么调节它们这样做的能力。在目标2中，我们将表征通过受体酪氨酸激酶Torso调节PTTH信号传导的额外的上游和下游输入。特别感兴趣的是，以确定是否PTTH配体加工所需的PTTH信号，如果PKC，PLC和IP 3受体，有助于PTTH信号在果蝇和他们的活动是如何耦合到躯干激活。在目标3中，我们将确定蜕皮激素生物合成酶phm，dib和spookier的调控区域中的关键转录控制元件，以了解PTTH信号如何调节蜕皮激素的产生。在aim 4中，我们将使用遗传学研究和成像方法来检验这一假设，即与目前的信念相反，蜕皮激素从前胸腺在变态蜕皮是一个囊泡介导的过程刺激PTTH。对人类健康的影响：在人类中，涉及类固醇激素的主要发育转变发生在青少年获得性成熟时。这种转变也是由神经肽信号结合营养和代谢线索控制的，尽管目前对这些信号如何整合以适当地确定转变时间知之甚少。这里描述的研究将有助于确定控制发育转变的基本分子程序，从而为理解这些过程如何在包括人类在内的脊椎动物中进行调节提供范例。此外，这些研究将为类固醇激素如何从内分泌细胞释放提供新的理解。 公共卫生相关性：这里描述的研究将有助于确定调节昆虫类固醇激素产生和分泌的基本分子程序。由于相关的发育过渡和类固醇释放机制发生在许多生物体，包括人类，这项工作将提供一个范例，了解不同的类固醇调节线索是如何整合的神经内分泌回路控制发展。

DESCRIPTION (provided by applicant): Proper development of all multi-cellular organisms requires not only correct spatial control of cellular interactions, but also correct timing of specific gene expression programs during development. Altering the timing of many developmental processes can significantly affect an animals final body size, reproductive ability and ageing. In insects, timing of developmental transitions, i.e. molting and metamorphosis, is mediated by 20-hydroxyecdysone (20E), a small circulating lipophilic steroid hormone that binds to and activates transcription factors of the nuclear receptor superfamily. Although the genetic hierarchy that controls responses to 20E has received considerable attention, little is presently known about mechanisms that control the timing of hormone production and its release. In this proposal we will determine how prothoraciotropic hormone, a peptide released from neurons that innervate the prothoracic gland (PGs) control hormone production and release. In aim 1 we will determine when the PG cells receive PTTH signals and what regulates their competence to do so. In aim 2 we will characterize additional upstream and downstream inputs that regulate PTTH signaling through the receptor tyrosine kinase Torso. Of particular interest is to determine if the PTTH ligand processing is required for PTTH signaling and if PKC, PLC and the IP3 receptor, contribute to PTTH signaling in Drosophila and how their activity is coupled to Torso activation. In aim 3, we will identify key transcriptional control elements in the regulatory regions of the ecdysone biosynthetic enzymes phm, dib and spookier, in order to learn how PTTH signals regulate ecdysone production. In aim4 we will use genetic studies and imaging methods to test the hypothesis that, contrary to present beliefs, release of ecdysone from the prothoracic gland during the metamorphic molt is a vesicle mediated process stimulated by PTTH. Impact on human health: In humans, a major developmental transition involving steroid hormones takes place as adolescents acquire sexual maturity. This transition is also controlled by a neuropeptide signal in conjunction with nutritional and metabolic cues, although little is presently known about how these signals are integrated to time the transition appropriately. The studies described here will help identify basic molecular programs that control developmental transitions and thereby provide a paradigm for understanding how these processes might be regulated in vertebrates including humans. In addition these studies will provide a new understanding of how steroid hormones are released from endocrine cells. PUBLIC HEALTH RELEVANCE: The studies described here will help identify basic molecular programs that regulate steroid hormone production and secretion in insects. Since related developmental transitions and steroid release mechanisms occur in many organisms, including humans, this work will provide a paradigm for understanding how different steroidogenic regulatory cues are integrated by the neuroendocrine circuit to control development.