A role for the Ecdysone receptor in hormonal control of Drosophila melanogaster midgut homeostasis and physiology.

蜕皮激素受体在果蝇中肠稳态和生理学激素控制中的作用。

• 批准号: 411066135
• 负责人: Dr. Tobias Reiff
• 金额: --
• 依托单位: Institut für Genetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/411066135?language=en
• 关键词: role; Ecdysone; receptor; hormonal; control

The proper maintenance and size-adaptation of adult organs is crucial to an organisms’ survival and competitivity for reproduction. Adult organs and tissues are fueled by a specialized cell type called adult stem cells (SC). SC are able to self-renew and multipotent, thus are able to generate all different cell types of their given tissue. The process of SC maintaining tissues function and size through constant division and tissue replenishment is called homeostasis, and relies on tight control of stem cell activity. For instance, epithelial damage stimulates SC division rate via local signaling pathways to replenish the tissue and therefore reestablish organ size and integrity. One of the most dramatic physiological adaptations to pregnancy and lactation is an increase in the size of the maternal mammalian intestine. Adaptation of the maternal intestine is a common feature in various taxonomic groups and ensures nutrient uptake during raised energy demand. Recently, we revealed that upon mating the release of 'juvenile hormone' (JH) from Drosophila melanogaster’s neuroendocrine corpus allatum leads to a larger resorptive surface through the expansion of the midgut epithelium by activating JH-receptors, resulting in intestinal SC (ISC) proliferation. On a broader scope, this finding suggests that adult organs can be remotely adapted by systemic signals to match new physiological conditions. Our preliminary experiments show that intestinal growth upon mating reaches a plateau and that the intestinal size adaptation is partially reversible when males are withdrawn. By a candidate gene approach, we identified the ecdysone steroid hormone receptor (EcR) inhibiting ISC proliferation using our recently developed tracing method 'ReDDM'. We aim to describe ecdysone signaling controlling midgut homeostasis during mating and male withdrawal. Additional preliminary data suggests that early ecdysone response genes E74A and E75B play a role in ISC as well. Furthermore, we will investigate the epistasis of EcR- and JH-signaling cascades that are known to antagonize each other during Drosophila development and investigate downstream effectors on which input from both pathways may converge. Taken together, our preliminary data suggests that the EcR-pathway plays a role in mating related intestinal adaptations in the fruit fly. Interestingly, female mice do not return to their pre-pregnancy weight and intestinal adaptations do not fully regress postpartum, leaving the intestine with higher nutrient resorption capability, possibly playing a role that weight retention. Excessive weight gain and postpartum weight retention are on the rise in western societies, increasing the risk of cardiovascular disease, metabolic syndrome and type II diabetes. By gaining a deeper understanding of pregnancy related intestinal adaptations, our hope is that in the long run treatments can be developed reducing short- and long-term medical complications for future mothers.

成体器官的适当维护和大小适应对于生物体的生存和繁殖竞争力至关重要。成体器官和组织由一种称为成体干细胞（SC）的特殊细胞类型提供燃料。SC能够自我更新和多能性，因此能够产生其给定组织的所有不同类型的细胞。SC通过不断分裂和组织补充来维持组织功能和大小的过程称为稳态，并且依赖于对干细胞活性的严格控制。例如，上皮损伤通过局部信号传导途径刺激SC分裂速率以补充组织并因此重建器官大小和完整性。妊娠和哺乳期最显著的生理适应之一是母体哺乳动物肠道尺寸的增加。母体肠道的适应是各种分类群的共同特征，并确保在能量需求增加时吸收营养。最近，我们发现，交配后释放的'保幼激素'（JH）从果蝇的神经内分泌体allatum导致一个更大的再吸收表面通过扩大中肠上皮细胞通过激活JH受体，导致肠SC（ISC）增殖。在更广泛的范围内，这一发现表明，成人器官可以通过系统信号远程适应新的生理条件。我们的初步实验表明，肠道生长交配后达到一个平台，肠道大小的适应是部分可逆的，当男性撤回。通过候选基因的方法，我们确定了蜕皮激素类固醇激素受体（EcR）抑制ISC增殖，使用我们最近开发的跟踪方法“RedDM”。我们的目的是描述蜕皮激素信号控制中肠稳态在交配和男性撤退。另外的初步数据表明，早期蜕皮激素反应基因E74A和E75B在ISC中也起作用。此外，我们将调查的上位性的EcR和JH信号级联，是已知的相互拮抗果蝇发育过程中，并调查下游效应器上的输入从两个途径可能会收敛。综上所述，我们的初步数据表明，ECR途径在果蝇交配相关的肠道适应中发挥作用。有趣的是，雌性小鼠不会恢复到怀孕前的体重，产后肠道适应性也不会完全消退，肠道具有更高的营养吸收能力，可能起到了保持体重的作用。在西方社会，体重过度增加和产后体重保持在上升趋势，增加了心血管疾病、代谢综合征和II型糖尿病的风险。通过更深入地了解与怀孕相关的肠道适应性，我们希望从长远来看，可以开发出减少未来母亲短期和长期医疗并发症的治疗方法。