BackgroundLymphotoxin (LT) is a lymphokine mainly expressed in lymphocytes. LTα binds one or two membrane-associated LTβ to form LTα2β1 or LTα1β2 heterotrimers. The predominant LTα1β2 binds to LTβ receptor (LTβR) primarily expressed in epithelial and stromal cells. Most studies on LTβR signaling have focused on the organization, development, and maintenance of lymphoid tissues. However, the roles of LTβR signaling in the nervous system, particularly in neurogenesis, remain unknown. Here, we investigated the role of LTβR-mediated NFκB signaling in regulating neural lineage differentiation.MethodsThe C57BL/6J wild-type and GFAP-dnIκBα transgenic mice were used. Serum-free embryoid bodies were cultured from mouse embryonic stem cells and further induced into neural stem/progenitor cells (NSCs/NPCs). Primary neurospheres were cultured from embryonic and adult mouse brains followed by monolayer culture for amplification/passage. NFκB activation was determined by adenovirus-mediated NFκB-firefly-luciferase reporter assay and p65/RelB/p52 nuclear translocation assay. LTβR mRNA expression was evaluated by quantitative RT-PCR and LTβR protein expression was determined by immunohistochemistry and Western blot analysis. Multilabeled immunocytochemistry or immunohistochemistry followed by fluorescent confocal microscopy and quantitative analysis of neural lineage differentiation were performed. Graphing and statistical analysis were performed with GraphPad Prism software.ResultsIn cultured NSCs/NPCs, LTα1β2 stimulation induced an activation of classical and non-classical NFκB signaling. The expression of LTβR-like immunoreactivity in GFAP+/Sox2+ NSCs was identified in well-established neurogenic zones of adult mouse brain. Quantitative RT-PCR and Western blot analysis validated the expression of LTβR in cultured NSCs/NPCs and brain neurogenic regions. LTβR expression was significantly increased during neural induction. LTα1β2 stimulation in cultured NSCs/NPCs promoted astroglial and oligodendrocytic lineage differentiation, but inhibited neuronal lineage differentiation. Astroglial NFκB inactivation in GFAP-dnIκBα transgenic mice rescued LTβR-mediated abnormal phenotypes of cultured NSCs/NPCs.ConclusionThis study provides the first evidence for the expression and function of LTβR signaling in NSCs/NPCs. Activation of LTβR signaling promotes glial lineage differentiation. Our results suggest that neurogenesis is regulated by the adaptive immunity and inflammatory responses.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1074-z) contains supplementary material, which is available to authorized users.

Long non-coding RNA (lncRNA) TP53 target 1 (TP53TG1) was discovered as a TP53 target gene. TP53TG1 has been reported as having dual roles by exerting tumor-suppressive and oncogenic activities that vary depending on the cancer type. Yet, the role of TP53TG1 in hepatocellular carcinoma (HCC) is not fully understood. In this study, we performed both gain- and loss-of-function studies to determine the biological role of TP53TG1 in HCC. We found that the knockdown of TP53 in HCC cells caused the upregulation of TP53TG1. Furthermore, we found that the knockdown of TP53TG1 not only suppressed HCC cell proliferation and migration, but also reduced intrinsic ERK signaling. In contrast, the overexpression of TP53TG1 increased ERK activation and enhanced HCC proliferation. In conclusion, our study reveals an oncogenic role of TP53TG1 in HCC, which provides a novel insight into the cell-type-specific function of TP53TG1 in HCC.

Limited Devonian magmatic record in northern West Junggar leads to contrasting models on its tectonic evolution. In this study, we conducted LA-ICP-MS U-Pb dating on detrital zircons of two sandstones from the Hebukesaier Formation in the Shaerbuerti Mountains. Detrital zircons with oscillatory zoning are characterized by high Th/U (> 0.3) and low La/Yb (< 0.15), indicating their magmatic origin. The youngest zircon ages of two samples are 402 ± 2 Ma and 406 ± 2 Ma, respectively, suggesting that the Hebukesaier Formation was deposited at the Early Devonian. Detrital zircon age patterns show single peaks (at ca. 424 Ma, n =157), which indicates that these clastics were likely proximal accumulation after short distance transportation. Provenance of the Hebukesaier Formation was the Xiemisitai and Shaerbuerti Mountains. Detrital zircon ages range from 481 Ma to 395 Ma, which indicates that there was relatively continuous Early Paleozoic magmatism in the Xiemisitai and Shaerbuerti Mountains since the Early Ordovician. Age spectrums of sampled detrital zircons are distinct from those of Lower Devonian strata either in southern West Junggar or in East Junggar, which implies for individual tectonic evolution of northern West Junggar. We favor that Lower Devonian Hebukesaier Formation was developed in a fore-arc setting due to the northward subduction of the Junggar-Balkhash Ocean.

Background The majority of mammalian genome is composed of non-coding regions, where numerous long non-coding RNAs (lncRNAs) are transcribed. Although lncRNAs have been identified to regulate fundamental biological processes, most of their functions remain unknown, especially in metabolic homeostasis. Analysis of our recent genome-wide screen reveals that Gm15441, a thioredoxin-interacting protein (Txnip) antisense lncRNA, is the most robustly induced lncRNA in the fasting mouse liver. Antisense lncRNAs are known to regulate their sense gene expression. Given that Txnip is a critical metabolic regulator of the liver, we aimed to investigate the role of Gm15441 in the regulation of Txnip and liver metabolism. Methods We examined the response of Gm15441 and Txnip under in vivo metabolic signals such as fasting and refeeding, and in vitro signals such as insulin and key metabolic transcription factors. We investigated the regulation of Txnip expression by Gm15441 and the underlying mechanism in mouse hepatocytes. Using adenovirus-mediated liver-specific overexpression, we determined whether Gm15441 regulates Txnip in the mouse liver and modulates key aspects of liver metabolism. Results We found that the expression levels of Gm15441 and Txnip showed a similar response pattern to metabolic signals in vivo and in vitro, but that their functions were predicted to be opposite. Furthermore, we found that Gm15441 robustly reduced Txnip protein expression in vitro through sequence-specific regulation and translational inhibition. Lastly, we confirmed the Txnip inhibition by Gm15441 in vivo (mice) and found that Gm15441 liver-specific overexpression lowered plasma triglyceride and blood glucose levels and elevated plasma ketone body levels. Conclusions Our data demonstrate that Gm15441 is a potent Txnip inhibitor and a critical metabolic regulator in the liver. This study reveals the therapeutic potential of Gm15441 in treating metabolic diseases.

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