No abstract

Endometriosis is an estrogen-dependent chronic inflammatory disease that affects approximately 10% of women of reproductive age and up to 50% of women with infertility. The heterogeneity of the disease makes accurate diagnosis and treatment a clinical challenge. In this study, we generated two models of endometriosis: the first in rats and the second using human ectopic endometrial stromal cells (HEcESCs) derived from the lesion tissues of endometriosis patients. We then applied resveratrol to assess its therapeutic potential. Resveratrol intervention had significant efficacy to attenuate lesion size and to rectify aberrant lipid profiles of model rats. Lipidomic analysis revealed significant lipidomic alterations, including notable increases of sphingolipids and decreases of both glycerolipids and most phospholipids. Upon resveratrol application, both proliferation capacity and invasiveness parameters decreased, and the early apoptosis proportion increased for HEcESCs. The activation of PPARα was also noted as a factor potentially contributing to recovery from endometriosis in both models. Our study provides valuable insight into the mechanisms of resveratrol in endometriosis and therefore strengthens the potential for optimizing resveratrol treatment for this disease.

By the end of neurogenesis in Drosophila pupal brain neuroblasts (NBs), nuclear Prospero (Pros) triggers cell cycle exit and terminates NB lifespan. Here, we reveal that in larval brain NBs, an intrinsic mechanism facilitates import and export of Pros across the nuclear envelope via a Ran‐mediated nucleocytoplasmic transport system. In rangap mutants, the export of Pros from the nucleus to cytoplasm is impaired and the nucleocytoplasmic transport of Pros becomes one‐way traffic, causing an early accumulation of Pros in the nuclei of the larval central brain NBs. This nuclear Pros retention initiates NB cell cycle exit and leads to a premature decrease of total NB numbers. Our data indicate that RanGAP plays a crucial role in this intrinsic mechanism that controls NB lifespan during neurogenesis. Our study may provide insights into understanding the lifespan of neural stem cells during neurogenesis in other organisms.

Edited by Mike Shipston Atg101 is an autophagy-related gene identified in worms, flies, mice, and mammals, which encodes a protein that functions in autophagosome formation by associating with the ULK1-Atg13-Fip200 complex. In the last few years, the critical role of Atg101 in autophagy has been well-established through biochemical studies and the determination of its protein structure. However, Atg101's physiological role, both during development and in adulthood, remains less understood. Here, we describe the generation and characterization of an Atg101 lossof-function mutant in Drosophila and report on the roles of Atg101 in maintaining tissue homeostasis in both adult brains and midguts. We observed that homozygous or hemizygous Atg101 mutants were semi-lethal, with only some of them surviving into adulthood. Both developmental and starvation-induced autophagy processes were defective in the Atg101 mutant animals, and Atg101 mutant adult flies had a significantly shorter lifespan and displayed a mobility defect. Moreover, we observed the accumulation of ubiquitin-positive aggregates in Atg101 mutant brains, indicating a neuronal defect. Interestingly, Atg101 mutant adult midguts were shorter and thicker and exhibited abnormal morphology with enlarged enterocytes. Detailed analysis also revealed that the differentiation from intestinal stem cells to enterocytes was impaired in these midguts. Cell type-specific rescue experiments disclosed that Atg101 had a function in enterocytes and limited their growth. In summary, the results of our study indicate that Drosophila Atg101 is essential for tissue homeostasis in both adult brains and midguts. We propose that Atg101 may have a role in age-related processes. Autophagy (macroautophagy) is a process in which cytoplasmic materials, including organelles and macromolecules, are delivered to and degraded in the lysosome (1-4). As a major intracellular degradation system, autophagy plays important roles in development, tissue homeostasis, and aging (5-7). Defects in the autophagy pathway cause various human diseases, such as cancer and neurodegenerative diseases (8-10). Genetic studies from budding yeast have identified more than 30 Atg genes, which function at various steps during autophagy (2, 3, 11). Most of these genes are highly conserved from yeast to mammals (3, 11). Among them, the Atg1 complex acts at the initiation stage of autophagy functioning as a scaffold for the recruitment of downstream Atg 2 proteins to the preautophagosomal structure (4, 11-13). The yeast Atg1 complex consists of Atg1, Atg13, Atg17, Atg29, and Atg31, and its mammalian counterpart is composed of ULK1 (or ULK2), Atg13, FIP200 (also known as RB1CC1) and Atg101 (4, 11-13). Mammalian ULK1 and ULK2 are homologs of Atg1 (13). FIP200 is generally considered as a homolog of yeast Atg11 and Atg17 (13). Homologs of Atg29 and Atg31 are not found in higher eukaryotes (13). In contrast, Atg101 is present in most eukaryotes, with the exception of budding yeast (13). It has been proposed that the regu...

The dynamic process of spermatogenesis shows little variation between invertebrate models such as Drosophila, and vertebrate models such as mice and rats. In each case, germ stem cells undergo mitotic division to proliferate and then continue, via meiosis, through various stages of elongation and individualization from spermatogonia to spermatid to finally to form mature sperm. Mature sperm are then stored in the seminal vesicles for fertilization. Errors in any of these stages can lead to male infertility. Here, we identify that Drosophila Pif1A acts as a key regulator for sperm individualization. Loss of Pif1A leads to male sterility associated with irregular individualization complex and empty seminal vesicles without mature sperm. Pif1A is highly expressed in the testes of mated male adult flies and the Pif1A protein is expressed at a higher level in male than in female flies. Pif1A is homologous to mammalian coiled-coil domain-containing protein 157 (CCDC157), which is also enriched in the testes of humans and mice. Human CCDC157, with unknown function, was identified to be downregulated in men with idiopathic non-obstructive azoospermia (NOA). We map the function of Drosophila Pif1A during spermatogenesis, showing that Pif1A is essential for spermatide individualization and involved in the regulation of the lipid metabolism genes. Our findings might be applicable for studying the function of CCDC157 in spermatogenesis and other aspects of human male fertility.

Summary Neuroprotection is essential for the maintenance of normal physiological functions in the nervous system. This is especially true under stress conditions. Here, we demonstrate a novel protective function of PRL-1 against CO 2 stimulation in Drosophila. In the absence of PRL-1, flies exhibit a permanent held-up wing phenotype upon CO 2 exposure. Knockdown of the CO 2 olfactory receptor, Gr21a, suppresses the phenotype. Our genetic data indicate that the wing phenotype is due to a neural dysfunction. PRL-1 physically interacts with Uex and controls Uex expression levels. Knockdown of Uex alone leads to a similar wing held-up phenotype to that of PRL-1 mutants. Uex acts downstream of PRL-1. Elevated Uex levels in PRL-1 mutants prevent the CO 2 -induced phenotype. PRL-1 and Uex are required for a wide range of neurons to maintain neuroprotective functions. Expression of human homologs of PRL-1 could rescue the phenotype in Drosophila , suggesting a similar function in humans.

In fat-body remodeling accompanied with fat mobilization is an ecdysone-induced dynamic process that only occurs during metamorphosis. Here, we show that the activated platelet-derived growth factor/VEGF receptor (PVR) is sufficient to induce shape changes in the fat body, from thin layers of tightly conjugated polygonal cells to clusters of disaggregated round-shaped cells. These morphologic changes are reminiscent of those seen during early pupation upon initiation of fat-body remodeling. Activation of PVR also triggers an early onset of lipolysis and mobilization of internal storage, as revealed by the appearance of small lipid droplets and up-regulated lipolysis-related genes. We found that PVR displays a dynamic expression pattern in the fat body and peaks at the larval-prepupal transition under the control of ecdysone signaling. Removal of PVR, although it does not prevent ecdysone-induced fat-body remodeling, causes ecdysone signaling to be up-regulated. Our data reveal that PVR is active in a dual-secured mechanism that involves an ecdysone-induced fat-body remodeling pathway and a reinforced PVR pathway for effective lipid mobilization. Ectopic expression of activated c-kit-the mouse homolog of PVR in the fat body-also results in a similar phenotype. This may suggest a novel function of c-kit as it relates to lipid metabolism in mammals.-Zheng, H., Wang, X., Guo, P., Ge, W., Yan, Q., Gao, W., Xi, Y., Yang, X. Premature remodeling of fat body and fat mobilization triggered by platelet-derived growth factor/VEGF receptor in.

CD133 (AC133/prominin‐l) has been identified as a stem cell marker and a putative cancer stem cell marker in many solid tumors. Its biologic function and molecular mechanisms remain largely elusive. Here, we show that a fly mutant for prominin‐like, a homolog of mammalian CD133, shows a larger body size and excess weight accompanied with higher fat deposits as compared with the wild type. The expression levels of prominin‐like are mediated by ecdysone signaling where its protein levels increase dramatically in the fat body during metamorphosis. Prominin‐like mutants exhibit higher Drosophila insulin‐like peptide 6 (dilp6) levels during nonfeeding stages and increased Akt/Drosophila target of rapamycin (dTOR) signaling. On an amino acid‐restricted diet, prominin‐like mutants exhibit a significantly larger body size than the wild type does, similar to that which occurs upon the activation of the dTOR pathway in the fat body. Our data suggest that prominin‐like functions by suppressing TOR and dilp6 signaling to control body size and weight. The identification of the physiologic function of prominin‐like in Drosophila may provide valuable insight into the understanding of the metabolic function of CD133 in mammals.—Zheng, H., Zhang, Y., Chen, Y., Guo, P., Wang, X., Yuan, X., Ge, W., Yang, R., Yan, Q., Yang, X., Xi, Y. Prominin‐like, a homolog of mammalian CD133, suppresses dilp6 and TOR signaling to maintain body size and weight in Drosophila. FASEB J. 33, 2646–2658 (2019). http://www.fasebj.org