The radial migration of neuronal progenitor cells is critical for the development of cerebral cortex layers. They go through a critical step transforming from multipolar to bipolar before outward migration. A Disintegrin and Metalloprotease 17 (ADAM17) is a transmembrane protease which can process many substrates involved in cell-cell interaction, including Notch, ligands of EGFR, and some cell adhesion molecules. In this study, we used in utero electroporation to knock down or overexpress ADAM17 at embryonic day 14.5 (E14.5) in neuronal progenitor cells to examine the role of ADAM17 in cortical embryonic neurogenesis. Our results showed that the radial migration of ADAM17-knocked down cells were normal till E16.5 and reached the intermediate zone (IZ). Then most transfected cells stopped migration and stayed at the IZ to inner cortical plate (CP) layer at E18.5, and there was higher percentage of multipolar cells at IZ layer in the ADAM17-knocked down group compared to the cells in control group. Marker staining revealed that those ADAM17-knocked down cells differentiated normally from neural stem cells (NSCs) to neuronal intermediate progenitor cells (nIPCs) but did not differentiate into mature neurons. The migration and multipolar exit defects caused by ADAM17 knockdown could be partially rescued by over-expressing an shRNA resistant ADAM17, while overexpressing ADAM17 alone did not affect the radial migration. Taken together, our results showed for the first time that, ADAM17 is critical in regulating the multipolar-stage exit and radial migration of the nIPCs during telencephalon cortex development in mice.

It has been proved that Uygur herb Hyssopus offcinalis L. could affect the levels of some cytokines (such as IL-4, IL-6, IL-17, and IFN-γ) in asthmatic mice. By detection of the expressions of MMP-9 and TIMP-1 and the morphological changes, the aim of this research is to reveal the mechanism of Uygur herb Hyssopus offcinalis L. in the process of airway remodeling. It was observed that the expressions of MMP-9 and TIMP-1 increased, but the ratio of MMP-9/TIMP-1 decreased in airway remodeling group. However, the expression of both MMP-9 and TIMP-1 decreased after being treated with dexamethasone and Hyssopus offcinalis L., accompanied by the relieved pathological changes, including collagen deposition, mucus secretion, and smooth muscle proliferation. It is suggested that Uygur herb Hyssopus offcinalis L. could inhibit airway remodeling by correcting imbalance of MMP-9/TIMP-1 ratio.

Disruptive mutations in chromatin remodeler CHD8 cause autism spectrum disorders, exhibiting widespread white matter abnormalities; however, the underlying mechanisms remain elusive. We show that cell-type specific Chd8 deletion in oligodendrocyte progenitors, but not in neurons, results in myelination defects, revealing a cell-intrinsic dependence on CHD8 for oligodendrocyte lineage development, myelination and post-injury remyelination. CHD8 activates expression of BRG1-associated SWI/SNF complexes that in turn activate CHD7, thus initiating a successive chromatin remodeling cascade that orchestrates oligodendrocyte lineage progression. Genomic occupancy analyses reveal that CHD8 establishes an accessible chromatin landscape, and recruits MLL/KMT2 histone methyltransferase complexes distinctively around proximal promoters to promote oligodendrocyte differentiation. Inhibition of histone demethylase activity partially rescues myelination defects of CHD8-deficient mutants. Our data indicate that CHD8 exhibits a dual function through inducing a cascade of chromatin reprogramming and recruiting H3K4 histone methyltransferases to establish oligodendrocyte identity, suggesting potential strategies of therapeutic intervention for CHD8-associated white matter defects.

Microcystin-LR (MCLR) is a potent hepatotoxin which could lead to the development of hepatocellular carcinoma. However, the mechanisms of its carcinogenic action remain obscure. The catalytic subunit of glutamylcysteine ligase (GCLC) primarily regulates de novo synthesis of glutathione and is central to the antioxidant capacity of the cell, but emerging data suggest that the GCLC expression is associated with cancer development. The purpose of this study was to investigate the role and molecular mechanisms of GCLC in MCLR-induced malignant transformation of a human liver cell line WRL68. During MCLR-induced cell transformation, the expression of GCLC and activity of glutamate-cysteine ligase (GCL) decreased continuously, accompanied with consistent low levels of glutathione (GSH) but high levels of oxidative DNA damages. Furthermore, MCLR markedly inhibited protein phosphatase 2 A (PP2 A), and increased the level of GCLC phosphorylation. In contrast, overexpression of GCLC significantly enhanced the levels of GSH, inhibited oxidative DNA damages, and suppressed MCLR-induced cell invasion and migration, as well as tumor growth in nude mice. GCLC overexpression partially attenuated MCLR-induced PP2 A inhibition. Together, the current results suggest that down-regulation of GCLC is involved in MCLR-induced malignant transformation of human liver cells by inducing oxidative stress.

DNA binding allosterically activates the cytosolic DNA sensor cGAS (cyclic GMP-AMP [cGAMP] synthase) to synthesize 2'3'-cGAMP, using Mg2+ as the metal cofactor that catalyzes two nucleotidyl-transferring reactions. We previously found that Mn2+ potentiates cGAS activation, but the underlying mechanism remains unclear. Here, we report that Mn2+ directly activates cGAS. Structural analysis reveals that Mn2+-activated cGAS undergoes globally similar conformational changes to DNA-activated cGAS but forms a unique η1 helix to widen the catalytic pocket, allowing substrate entry and cGAMP synthesis. Strikingly, in Mn2+-activated cGAS, the linear intermediates pppGpG and pGpA take an inverted orientation in the active pocket, suggesting a noncanonical but accelerated cGAMP cyclization without substrate flip-over. Moreover, unlike the octahedral coordination around Mg2+, the two catalytic Mn2+ are coordinated by triphosphate moiety of the inverted substrate, independent of the catalytic triad residues. Our findings thus uncover Mn2+ as a cGAS activator that initiates noncanonical 2'3'-cGAMP synthesis.

A lack of sufficient oligodendrocyte myelination contributes to remyelination failure in demyelinating disorders. miRNAs have been implicated in oligodendrogenesis; however, their functions in myelin regeneration remained elusive. Through developmentally regulated targeted mutagenesis, we demonstrate that miR-219 alleles are critical for CNS myelination and remyelination after injury. Further deletion of miR-338 exacerbates the miR-219 mutant hypomyelination phenotype. Conversely, miR-219 overexpression promotes precocious oligodendrocyte maturation and regeneration processes in transgenic mice. Integrated transcriptome profiling and biotin-affinity miRNA pull-down approaches reveal stage-specific miR-219 targets in oligodendrocytes and further uncover a novel network for miR-219 targeting of differentiation inhibitors including Lingo1 and Etv5. Inhibition of Lingo1 and Etv5 partially rescues differentiation defects of miR-219-deficient oligodendrocyte precursors. Furthermore, miR-219 mimics enhance myelin restoration following lysolecithin-induced demyelination as well as experimental autoimmune encephalomyelitis, principal animal models of multiple sclerosis. Together, our findings identify context-specific miRNA-regulated checkpoints that control myelinogenesis and a therapeutic role for miR-219 in CNS myelin repair.

Establishment and maintenance of CNS glial cell identity ensures proper brain development and function, yet the epigenetic mechanisms underlying glial fate control remain poorly understood. Here, we show that the histone deacetylase Hdac3 controls oligodendrocyte-specification gene Olig2 expression and functions as a molecular switch for oligodendrocyte and astrocyte lineage determination. Hdac3 ablation leads to a significant increase of astrocytes with a concomitant loss of oligodendrocytes. Lineage tracing indicates that the ectopic astrocytes originate from oligodendrocyte progenitors. Genome-wide occupancy analysis reveals that Hdac3 interacts with p300 to activate oligodendroglial lineage-specific genes, while suppressing astroglial differentiation genes including NFIA. Furthermore, we find that Hdac3 modulates the acetylation state of Stat3 and competes with Stat3 for p300 binding to antagonize astrogliogenesis. Thus, our data suggest that Hdac3 cooperates with p300 to prime and maintain oligodendrocyte identity while inhibiting NFIA and Stat3-mediated astrogliogenesis, and thereby regulates phenotypic commitment at the point of oligodendrocyte-astrocytic fate decision.

The Uygur herb, Hyssopus officinalis L., has been demonstrated to affect the levels of a number of cytokines in asthmatic mice, including interleukin-4, -6 and -17 and interferon-γ. In the present study, the effect of Hyssopus officinalis L. on airway immune regulation and airway inflammation was investigated in a mouse model of chronic asthma. A total of 32 BALB/c mice were randomly divided into four groups, which included the normal, chronic asthmatic, dexamethasone treatment and Hyssopus officinalis L.treatment groups. Mice were sensitized and challenged with ovalbumin to establish an asthma model and the ratio of eosinophils (EOS) in the bronchoalveolar lavage fluid (BALF) was determined. In addition, the levels of immunoglobulin (Ig)E and IgG were detected using an enzyme-linked immunosorbent assay. The degree of airway mucus secretion was observed using the periodic acid-Schiff stain method. The results demonstrated that the ratio of EOS in the BALF and the level of serum IgE in the chronic asthmatic and dexamethasone treatment groups increased, while the level of serum IgG decreased, when compared with the normal group. In addition, excessive secretion of airway mucus was observed in these two groups. However, the EOS ratio in the BALF and the levels of serum IgE and IgG in the Hyssopus officinalis L. treatment group were similar to the results observed in the normal group. In conclusion, Hyssopus officinalis L. not only plays an anti-inflammatory role by inhibiting the invasion of EOS and decreasing the levels of IgE, but also affects immune regulation.

The multiple-layer structure of the cerebral cortex is important for its functions. Such a structure is generated based on the proliferation and differentiation of neural stem/progenitor cells. Notch functions as a molecular switch for neural stem/progenitor cell fate during cortex development but the mechanism remains unclear. Biochemical and cellular studies showed that Notch receptor activation induces several proteases to release the Notch intracellular domain (NICD). A Disintegrin and Metalloprotease 10 (ADAM10) might be a physiological rate-limiting S2 enzyme for Notch activation. Nestin-driven conditional ADAM10 knockout in mouse cortex showed that ADAM10 is critical for maintenance of the neural stem cell population during early embryonic cortex development. However, the expression pattern and function of ADAM10 during later cerebral cortex development remains poorly understood. We performed in situ hybridization for ADAM10 mRNA and immunofluorescent analysis to determine the expression of ADAM10 and NICD in mouse cortex from embryonic day 9 (E14.5) to postnatal day 1 (P1). ADAM10 and NICD were highly co-localized in the cortex of E16.5 to P1 mice. Comparisons of expression patterns of ADAM10 with Nestin (neural stem cell marker), Tuj1 (mature neuron marker), and S100β (glia marker) showed that ADAM10 expression highly matched that of S100β and partially matched that of Tuj1 at later embryonic to early postnatal cortex developmental stages. Such expression patterns indicated that ADAM10-Notch signaling might have a critical function in neuronal maturation and gliogenesis during cortex development.

Protein phosphatase 2A (PP2A, a serine/threonine phosphatase) is frequently inactivated in many types of cancer, including primary liver cancer (PLC). Genetic variations in PP2A subunits have been reported to be associated with the risk of many types of cancer but rarely in PLC. This study aims to assess the association between functional polymorphisms of PP2A subunit genes and the risk of PLC in Chinese.