Control of developmental timing and body size in Drosophila

果蝇发育时间和体型的控制

• 批准号: 8133080
• 负责人: MICHAEL Brendan O'CONNOR
• 金额: $ 35.74万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133080
• 关键词: Activins; Address; Adolescent; Affect; Age; Animals; Attention; Belief; Binding; Biological Metamorphosis; Body Size; Cells; Competence; Coupled; Cues; Development; Developmental Process; Drosophila genus; Ecdysone; Ecdysterone; Endocrine; Enzymes; Event; Gene Expression; Genetic; Gland; Growth Factor; Health; Hormones; Human; Indium; Insect Control; Insecta; Learning; Lepidoptera; Ligands; Light; MAP Kinase Gene; Mammals; Mediating; Mediator of activation protein; Metabolic; Molecular; Molting; Neurons; Neuropeptides; Neurosecretory Systems; Nuclear Receptors; Nucleic Acid Regulatory Sequences; Nutritional; Organism; Peptides; Physiologic pulse; Process; Production; Puberty; Receptor Protein-Tyrosine Kinases; Signal Transduction; Staging; Steroid biosynthesis; Steroids; System; Testing; Time; Transcriptional Regulation; Vertebrates; Vesicle; Work; activating transcription factor; hormone control mechanism; imaging modality; interest; programs; public health relevance; receptor; reproductive; research study; response; steroid hormone; trafficking

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.

描述（由申请人提供）：所有多细胞生物的适当开发不仅需要对细胞相互作用的正确空间控制，而且还需要正确的开发过程中特定基因表达程序的时机。改变许多发育过程的时机可以显着影响动物的最终身体大小，生殖能力和衰老。在昆虫中，发育过渡的时机，即或越变质的时间，是由20-羟基甲虫（20E）介导的，这是一种小循环的亲脂性类固醇激素，可与核受体的转录因子结合并激活核受体超家族的转录因子。尽管控制对20E的响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时间及其释放的机制知之甚少。在此提案中，我们将确定丙型抗激素激素是从神经元释放的一种肽，该激素如何支配促腺（PGS）控制激素的产生和释放。在AIM 1中，我们将确定PG单元何时接收PTTH信号，以及如何调节其能力。在AIM 2中，我们将表征通过受体酪氨酸激酶躯干调节PTTH信号传导的其他上游和下游输入。特别感兴趣的是确定PTTH信号传导是否需要PTTH配体处理，以及PKC，PLC和IP3受体是否有助于果蝇中的PTTH信号，以及它们的活性如何与躯干激活耦合。在AIM 3中，我们将确定ecdysone Biosynthetic酶PHM，DIB和Spookier的调节区域中的关键转录控制元件，以了解PTTH信号如何调节Ecdysone的生产。在AIM4中，我们将使用遗传研究和成像方法来检验以下假设：与当前的信念相反，在变质蜕皮期间，ecdysone释放了ecdysone从胸膜腺释放，是PTTH刺激的囊泡介导的过程。对人类健康的影响：在人类中，当青少年获得性成熟时，涉及类固醇激素的主要发展过渡发生。这种过渡也由神经肽信号与营养和代谢线索结合使用，尽管目前对这些信号如何整合到适当的时间过渡时几乎不知所措。此处描述的研究将有助于确定控制发育过渡的基本分子程序，从而为了解如何在包括人类在内的脊椎动物中调节这些过程的范例。此外，这些研究将对内分泌细胞释放类固醇激素的新了解。 公共卫生相关性：此处描述的研究将有助于确定基本的分子程序，以调节昆虫中类固醇激素的产生和分泌。由于包括人类在内的许多生物发生了相关的发育过渡和类固醇释放机制，因此这项工作将提供一个范式，以了解神经内分泌电路如何整合不同的类固醇调节线索以控制发育。