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

成体器官的适当维护和大小适应对生物体的生存和繁殖竞争力至关重要。成体器官和组织是由一种叫做成体干细胞（SC）的特殊细胞提供能量的。SC具有自我更新和多能性，因此能够在其给定组织中产生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被称为稳态，它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通路刺激SC分裂率来补充组织，从而重建器官的大小和完整性。对怀孕和哺乳最显著的生理适应之一是母体哺乳动物肠道大小的增加。母肠的适应性是各种分类类群的共同特征，并确保在能量需求增加时营养吸收。最近，我们发现交配后，黑腹果蝇神经内分泌异位体释放的“幼体激素”（JH）通过激活JH受体，通过扩大中肠上皮，导致更大的吸收表面，从而导致肠道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进行远程调整，以适应新的生理条件。我们的初步实验表明，交配后肠道的生长达到一个平台期，当雄性退出时，肠道大小的适应是部分可逆的。通过候选基因方法，我们使用我们最近开发的追踪方法“ReDDM”确定了抑制ISC增殖的蜕皮激素类固醇激素受体（EcR）。我们的目的是描述蜕皮激素信号控制中肠稳态在交配和雄性退出。另外的初步数据表明，早期蜕皮激素反应基因E74A和E75B也在ISC中发挥作用。此外，我们将研究EcR-和jh信号级联的上位性，这两种信号级联在果蝇发育过程中相互拮抗，并研究这两种途径的输入可能会聚的下游效应物。综上所述，我们的初步数据表明，ecr通路在果蝇交配相关的肠道适应中发挥了作用。有趣的是，雌性小鼠不会恢复到怀孕前的体重，肠道的适应性也不会在产后完全恢复，这使得肠道具有更高的营养吸收能力，可能起到了体重保持的作用。在西方社会，体重过度增加和产后体重潴留正在增加，这增加了患心血管疾病、代谢综合征和II型糖尿病的风险。通过对妊娠相关肠道适应性的更深入了解，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。

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.