Follicle-stimulating hormone receptor (FSHR) and its intracellular signaling control mammalian follicular development and female infertility. Our previous study showed that FSHR is downregulated during follicular atresia of porcine ovaries. However, its role and regulation in follicular atresia remain unclear. Here, we showed that FSHR knockdown induced porcine granulosa cell (pGC) apoptosis and follicular atresia, and attenuated the levels of intracellular signaling molecules such as PKA, AKT and p-AKT. FSHR was identified as a target of miR-143, a microRNA that was upregulated during porcine follicular atresia. miR-143 enhanced pGC apoptosis by targeting FSHR, and reduced the levels of intracellular signaling molecules. SMAD4, the final molecule in transforming growth factor (TGF)-β signaling, bound to the promoter and induced significant downregulation of miR-143 in vitro and in vivo. Activated TGF-β signaling rescued miR-143-reduced FSHR and intracellular signaling molecules, and miR-143-induced pGC apoptosis. Overall, our findings offer evidence to explain how TGF-β signaling influences and FSHR signaling for regulation of pGC apoptosis and follicular atresia by a specific microRNA, miR-143.
BackgroundChemokine CXC receptor 4 (CXCR4) in spinal glial cells has been implicated in neuropathic pain. However, the regulatory cascades of CXCR4 in neuropathic pain remain elusive. Here, we investigated the functional regulatory role of miRNAs in the pain process and its interplay with CXCR4 and its downstream signaling.MethodsmiRNAs and CXCR4 and its downstream signaling molecules were measured in the spinal cords of mice with sciatic nerve injury via partial sciatic nerve ligation (pSNL). Immunoblotting, immunofluorescence, immunoprecipitation, and mammal two-hybrid and behavioral tests were used to explore the downstream CXCR4-dependent signaling pathway.ResultsCXCR4 expression increased in spinal glial cells of mice with pSNL-induced neuropathic pain. Blocking CXCR4 alleviated the pain behavior; contrarily, overexpressing CXCR4 induced pain hypersensitivity. MicroRNA-23a-3p (miR-23a) directly bounds to 3′ UTR of CXCR4 mRNA. pSNL-induced neuropathic pain significantly reduced mRNA expression of miR-23a. Overexpression of miR-23a by intrathecal injection of miR-23a mimics or lentivirus reduced spinal CXCR4 and prevented pSNL-induced neuropathic pain. In contrast, knockdown of miR-23a by intrathecal injection of miR-23a inhibitor or lentivirus induced pain-like behavior, which was reduced by CXCR4 inhibition. Additionally, miR-23a knockdown or CXCR4 overexpression in naïve mice could increase the thioredoxin-interacting protein (TXNIP), which was associated with induction of NOD-like receptor protein 3 (NLRP3) inflammasome. Indeed, CXCR4 and TXNIP were co-expressed. The mammal two-hybrid assay revealed the direct interaction between CXCR4 and TXNIP, which was increased in the spinal cord of pSNL mice. In particular, inhibition of TXNIP reversed pain behavior elicited by pSNL, miR-23a knockdown, or CXCR4 overexpression. Moreover, miR-23a overexpression or CXCR4 knockdown inhibited the increase of TXNIP and NLRP3 inflammasome in pSNL mice.ConclusionsmiR-23a, by directly targeting CXCR4, regulates neuropathic pain via TXNIP/NLRP3 inflammasome axis in spinal glial cells. Epigenetic interventions against miR-23a, CXCR4, or TXNIP may potentially serve as novel therapeutic avenues in treating peripheral nerve injury-induced nociceptive hypersensitivity.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1073-0) contains supplementary material, which is available to authorized users.
Emerging evidence has shown that miRNA-mediated gene expression modulation contributes to chronic pain, but its functional regulatory mechanism remains unknown. Here, we found that complete
Canonical TGF-β signals are transduced from the cell surface to the cytoplasm, and then translocated into the nucleus, a process that involves ligands (TGF-β1), receptors (TGFBR2/1), receptor-activated SMADs (SMAD2/3), and the common SMAD (SMAD4). Here we provide evidence that SMAD4, a core component of the canonical TGF-β signaling pathway, regulates the canonical TGF-β signaling pathway in porcine granulosa cells (GCs) through a feedback mechanism. Genome-wide analysis and qRT-PCR revealed that SMAD4 affected miRNA biogenesis in GCs. Interestingly, TGFBR2, the type II receptor of the canonical TGF-β signaling pathway, was downregulated in SMAD4-silenced GCs and found to be a common target of SMAD4-inhibited miRNAs. miR-425, the most significantly elevated miRNA in SMAD4-silenced GCs, mediated the SMAD4 feedback regulation of the TGF-β signaling pathway. This was accomplished through a direct interaction between the transcription factor SMAD4 and the miR-425 promoter, and a direct interaction between miR-425 and the TGFBR2 3′-UTR. Furthermore, miR-425 enhanced GC apoptosis by targeting TGFBR2 and the canonical TGF-β signaling pathway, which was rescued by SMAD4 and TGF-β1. Overall, our findings demonstrate that a positive feedback mechanism exists within the canonical TGF-β signaling pathway. This study also provides new insights into mechanism underlying the canonical TGF-β signaling pathway, which regulates GC function and follicular development.
The water buffalo is vital to the lives of small farmers and to the economy of many countries worldwide. Not only are they draught animals, but they are also a source of meat, horns, skin and particularly the rich and precious milk that may be converted to creams, butter, yogurt and many cheeses. Genome analysis of water buffalo has advanced significantly in recent years. This review focuses on currently available genome resources in water buffalo in terms of cytogenetic characterization, whole genome mapping and next generation sequencing. No doubt, these resources indicate that genome science comes of age in the species and will provide knowledge and technologies to help optimize production potential, reproduction efficiency, product quality, nutritional value and resistance to diseases. As water buffalo and domestic cattle, both members of the Bovidae family, are closely related, the vast amount of cattle genetic/genomic resources might serve as shortcuts for the buffalo community to further advance genome science and biotechnologies in the species.
MicroRNAs (miRNAs) are short, noncoding RNAs that posttranscriptionally regulate gene expression. In the past decade, studies on miRNAs in ovaries have revealed the key roles of miRNAs in ovarian development and function. In this review, we first introduce the development of follicular atresia research and then summarize genome-wide studies on the ovarian miRNA profiles of different mammalian species. Differentially expressed miRNA profiles during atresia and other biological processes are herein compared. In addition, current knowledge on confirmed functional miRNAs during the follicular atresia process, which is mostly indicated by granulosa cell (GC) apoptosis, is presented. The main miRNA families and clusters, including the let-7 family, miR-23-27-24 cluster, miR-183-96-182 cluster and miR-17-92 cluster, and related pathways that are involved in follicular atresia are thoroughly summarized. A deep understanding of the roles of miRNA networks will not only help elucidate the mechanisms of GC apoptosis, follicular development, atresia and their disorders but also offer new diagnostic and treatment strategies for infertility and other ovarian dysfunctions.Electronic supplementary materialThe online version of this article (10.1186/s12958-018-0450-y) contains supplementary material, which is available to authorized users.
Sma- and Mad-related protein 4 (SMAD4) is the central mediator of the transforming growth factor beta signaling pathway and is closely related to mammalian reproductive ability and the development of ovarian follicles. However, little is currently known about the role of SMAD4 in mammalian follicular granulosa cell (GC) apoptosis or its regulation by miRNAs. Here, we found that the porcine SMAD4 protein was expressed at high levels in GCs and oocytes from primary, preantral, and antral follicles, and only slightly expressed in theca cells; its expression level was down-regulated in apoptotic ovarian GCs, suggesting that SMAD4 may be involved in ovary development and selection. Overexpression and knockdown of SMAD4 increased the proliferation and apoptosis of cultured porcine GCs, respectively. In addition, the use of miRNA mimics and luciferase reporter assays revealed that miRNA-26b (miR-26b) functions as a proapoptotic factor in porcine follicular GCs by targeting the 3'-untranslated region of the SMAD4 gene. Overexpression of miR-26b in follicular GCs suppressed SMAD4 mRNA and protein levels, resulting in down-regulation of the antiapoptotic BCL-2 gene and the promotion of GC apoptosis. Furthermore, transforming growth factor beta 1 (TGF-beta1) down-regulates miR-26b expression in porcine GCs. Taken together, these data suggest that SMAD4 plays a critical role in porcine follicular GC apoptosis and follicular atresia and that miR-26b may have a proapoptotic role in GCs by regulating the expression of SMAD4 in the transforming growth factor beta signaling pathway.
Biomimetic assembly of high-quality nanosheets into nacre-like structures can produce macroscopic films with favorable mechanical and optical performances due to the intrinsic properties and high level of ordering of the nanoscale building blocks. Natural ground mica is abundant and exhibits great application potential. However, large size and low aspect ratio greatly limit its biomimetic assembly. Moreover, exfoliation of ground mica into high-quality nanosheets remains a significant challenge. Here, we report that large-scale exfoliation of ground mica into mono- or few-layered mica nanosheets with a production rate of ~1.0 g h−1 can be successfully achieved. The mica nanosheets are then assembled into strong biomimetic polymeric mica film that inherits the high electric insulation, excellent visible transmittance, and unique ultraviolet-shielding properties of natural mica. Its overall performance is superior to that of natural sheet mica and other biomimetic films, making the polymeric mica film a suitable substrate for flexible and transparent devices.
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