Unraveling the Prognostic Significance of Rgs Gene Family in Gastric Cancer and the Potential Implication of Rgs4 in Regulating Tumor-infiltrating Fibroblast

Regulator of G-protein signaling (RGS) proteins are regulators of signal transduction mediated by G protein-coupled receptors (GPCRs). Current studies have shown that some molecules in the RGS gene family are related to the occurrence, development and poor prognosis of malignant tumors. However, the RGS gene family has been rarely studied in gastric cancer. In this study, we explored the mutation and expression profile of RGS gene family in gastric cancer, and evaluated the prognostic value of RGS expression. Then we established a prognostic model based on RGS gene family and performed functional analysis. Further studies showed that RGS4, as an independent prognostic predictor, may play an important role in regulating fibroblasts in the immune microenvironment. In conclusion, this study explores the value of RGS gene family in gastric cancer, which is of great significance for predicting the prognosis and guiding the treatment of gastric cancer

Unraveling the prognostic significance of RGS gene family in gastric cancer and the potential implication of RGS4 in regulating tumor-infiltrating fibroblast

Regulator of G-protein signaling (RGS) proteins are regulators of signal transduction mediated by G protein-coupled receptors (GPCRs). Current studies have shown that some molecules in the RGS gene family are related to the occurrence, development and poor prognosis of malignant tumors. However, the RGS gene family has been rarely studied in gastric cancer. In this study, we explored the mutation and expression profile of RGS gene family in gastric cancer, and evaluated the prognostic value of RGS expression. Then we established a prognostic model based on RGS gene family and performed functional analysis. Further studies showed that RGS4, as an independent prognostic predictor, may play an important role in regulating fibroblasts in the immune microenvironment. In conclusion, this study explores the value of RGS gene family in gastric cancer, which is of great significance for predicting the prognosis and guiding the treatment of gastric cancer

Targeted ablation of oligodendrocytes induces axonal pathology independent of overt demyelination

The critical role of oligodendrocytes in producing and maintaining myelin that supports rapid axonal conduction in CNS neurons is well established. More recently, additional roles for oligodendrocytes have been posited, including provision of trophic factors and metabolic support for neurons. To investigate the functional consequences of oligodendrocyte loss, we have generated a transgenic mouse model of conditional oligodendrocyte ablation. In this model, oligodendrocytes are rendered selectively sensitive to exogenously administered diphtheria toxin (DT) by targeted expression of the diphtheria toxin receptor in oligodendrocytes. Administration of DT resulted in severe clinical dysfunction with an ascending spastic paralysis ultimately resulting in fatal respiratory impairment within 22 d of DT challenge. Pathologically, at this time point, mice exhibited a loss of ∼26% of oligodendrocyte cell bodies throughout the CNS. Oligodendrocyte cell-body loss was associated with moderate microglial activation, but no widespread myelin degradation. These changes were accompanied with acute axonal injury as characterized by structural and biochemical alterations at nodes of Ranvier and reduced somatosensory-evoked potentials. In summary, we have shown that a death signal initiated within oligodendrocytes results in subcellular changes and loss of key symbiotic interactions between the oligodendrocyte and the axons it ensheaths. This produces profound functional consequences that occur before the removal of the myelin membrane, i.e., in the absence of demyelination. These findings have clear implications for the understanding of the pathogenesis of diseases of the CNS such as multiple sclerosis in which the oligodendrocyte is potentially targeted

Investigation of the relative contribution of neural precursor cells and oligodendrocyte progenitor cells to myelin repair

© 2015 Dr. Yao Lulu XingRemyelination following demyelination of the central nervous system is mediated via the generation of new myelin-forming oligodendrocytes. It has been demonstrated that both parenchymal oligodendrocyte progenitor cells (OPCs) and neural precursor cells (NPCs) that reside in the adult subventricular zone (SVZ) contribute to oligodendrocyte regeneration. However, the relative contribution of each progenitor cell population to oligodendrogenesis and remyelination of demyelinated lesions remains unknown. I have used an in vivo genetic fate-mapping approach to assess the spatiotemporal dynamics of oligodendrogenesis and remyelination by OPCs and NPCs within the corpus callosi (CC) of mice subjected to cuprizone-induced demyelination. Nestin-CreERT2 and Pdgfra-CreERT2 mice were crossed with fluorescent Cre reporter strains to map the fate of NPCs and OPCs, respectively. In cuprizone-challenged mice, substantial numbers of NPCs migrated into the demyelinated CC and the vast majority of cells differentiated into mature oligodendrocytes. This capacity was most prominent in the rostral regions adjacent to the SVZ where NPC-derived oligodendrocytes outnumbered those generated from OPCs. OPC-derived oligodendrocytes at recovery were distributed in a converse manner to NPC-derived cells. Sixty-two percent of all nodes of Ranvier adjacent to the SVZ were flanked by at least one paranode myelinated by an NPC-derived oligodendrocyte, which contributed to the formation of nodal clusters of Nav1.6 channels despite diffused localisation of paranodal Caspr proteins. An extended analysis of morphological characteristics of the newly-synthesised myelin generated by each progenitor cell population has demonstrated that NPC-derived oligodendrocytes elaborated many more, shorter myelin internodes than OPC-derived counterparts. Compared to unchallenged controls, g-ratios of myelinated fibers in regions adjacent to the SVZ were equivalent. Importantly, fate-mapping followed by immunoelectron microscopy provided definitive evidence that NPC-derived myelin was substantially thicker than that generated by parenchymal OPCs and was indistinguishable from normal healthy myelin. Immunohistochemical analysis also revealed that NPC-mediated oligodendrogenesis was associated with a higher proportion of immature oligodendrocytes exhibiting phospho-Erk1/2 and phospho-Akt signalling activity, which are known to positively regulate myelin thickness during postnatal development. This finding raises the possibility that enhanced Erk1/2 and Akt signaling in oligodendrogenic NPCs could endow these cells with the capacity to regenerate myelin of normal thickness. In addition, I have developed a novel transgenic mouse model of conditional OPC ablation for future studies of NPC function after demyelination. To achieve this, I crossed Pdgfra-CreERT2 mice with a Cre-conditional cell ablation line called Sox10-lox-GFP-STOP-lox-DTA (denoted Sox10-DTA). Administration of tamoxifen to double heterozygous mice induced the expression of diphtheria toxin fragment A (DTA) in OPCs which resulted in apoptosis of many OPCs. To prevent regeneration of the OPC population from the non-ablated OPC population, I then infused the anti-mitotic drug cytosine-β-D-arabinofuranoside (AraC) intracisternally resulting in successful ablation of the entire OPC population without subsequent cell regeneration. Although AraC administration also ablated constitutively proliferating NPCs in the SVZ, this effect was only transient reflected by completely replenishment of SVZ neuroblasts to control levels within 10 days post AraC infusion. In line with previous reports on the effect of AraC administration on neurogenesis in the SVZ, these observations are consistent with the activation of quiescent neural stem cells in the SVZ following AraC withdrawal and subsequenct repopulation of the SVZ with newly generated NPCs. In the future, this protocol of highly efficient selective OPC ablation could be adopted in the context of cuprizone-induced demyelination to establish the influence of OPC ablation upon the regenerative capacity and function of NPC-derived oligodendrocytes. In conclusion, this thesis presents compelling evidence in support of an unappreciated role of endogenous NPCs in remyelination of denuded axons in the mouse model of cuprizone-induced demyelination and shed light on possible candidate molecular mediators that could be responsible for the morphological differences between OPC- and NPC-derived myelin. The generation of a novel mouse model for selectively abating OPCs while sparing NPCs by a combination of transgenic and pharmacological techniques provides further opportunity to understand the functional significance of remyelination mediated by NPC-derived oligodendrocytes. Collectively, the studies described in this thesis have important implications for the development new therapeutic options to promote efficient myelin repair in demyelinating diseases such as multiple sclerosis

Image2_Unraveling the prognostic significance of RGS gene family in gastric cancer and the potential implication of RGS4 in regulating tumor-infiltrating fibroblast.pdf

Regulator of G-protein signaling (RGS) proteins are regulators of signal transduction mediated by G protein-coupled receptors (GPCRs). Current studies have shown that some molecules in the RGS gene family are related to the occurrence, development and poor prognosis of malignant tumors. However, the RGS gene family has been rarely studied in gastric cancer. In this study, we explored the mutation and expression profile of RGS gene family in gastric cancer, and evaluated the prognostic value of RGS expression. Then we established a prognostic model based on RGS gene family and performed functional analysis. Further studies showed that RGS4, as an independent prognostic predictor, may play an important role in regulating fibroblasts in the immune microenvironment. In conclusion, this study explores the value of RGS gene family in gastric cancer, which is of great significance for predicting the prognosis and guiding the treatment of gastric cancer.</p

Image1_Unraveling the prognostic significance of RGS gene family in gastric cancer and the potential implication of RGS4 in regulating tumor-infiltrating fibroblast.pdf

Regulator of G-protein signaling (RGS) proteins are regulators of signal transduction mediated by G protein-coupled receptors (GPCRs). Current studies have shown that some molecules in the RGS gene family are related to the occurrence, development and poor prognosis of malignant tumors. However, the RGS gene family has been rarely studied in gastric cancer. In this study, we explored the mutation and expression profile of RGS gene family in gastric cancer, and evaluated the prognostic value of RGS expression. Then we established a prognostic model based on RGS gene family and performed functional analysis. Further studies showed that RGS4, as an independent prognostic predictor, may play an important role in regulating fibroblasts in the immune microenvironment. In conclusion, this study explores the value of RGS gene family in gastric cancer, which is of great significance for predicting the prognosis and guiding the treatment of gastric cancer.</p

Table1_Unraveling the prognostic significance of RGS gene family in gastric cancer and the potential implication of RGS4 in regulating tumor-infiltrating fibroblast.docx

Regulator of G-protein signaling (RGS) proteins are regulators of signal transduction mediated by G protein-coupled receptors (GPCRs). Current studies have shown that some molecules in the RGS gene family are related to the occurrence, development and poor prognosis of malignant tumors. However, the RGS gene family has been rarely studied in gastric cancer. In this study, we explored the mutation and expression profile of RGS gene family in gastric cancer, and evaluated the prognostic value of RGS expression. Then we established a prognostic model based on RGS gene family and performed functional analysis. Further studies showed that RGS4, as an independent prognostic predictor, may play an important role in regulating fibroblasts in the immune microenvironment. In conclusion, this study explores the value of RGS gene family in gastric cancer, which is of great significance for predicting the prognosis and guiding the treatment of gastric cancer.</p

Image3_Unraveling the prognostic significance of RGS gene family in gastric cancer and the potential implication of RGS4 in regulating tumor-infiltrating fibroblast.pdf

Regulator of G-protein signaling (RGS) proteins are regulators of signal transduction mediated by G protein-coupled receptors (GPCRs). Current studies have shown that some molecules in the RGS gene family are related to the occurrence, development and poor prognosis of malignant tumors. However, the RGS gene family has been rarely studied in gastric cancer. In this study, we explored the mutation and expression profile of RGS gene family in gastric cancer, and evaluated the prognostic value of RGS expression. Then we established a prognostic model based on RGS gene family and performed functional analysis. Further studies showed that RGS4, as an independent prognostic predictor, may play an important role in regulating fibroblasts in the immune microenvironment. In conclusion, this study explores the value of RGS gene family in gastric cancer, which is of great significance for predicting the prognosis and guiding the treatment of gastric cancer.</p

Amyloid precursor protein and amyloid precursor-like protein 2 have distinct roles in modulating myelination, demyelination, and remyelination of axons

The identification of factors that regulate myelination provides important insight into the molecular mechanisms that coordinate nervous system development and myelin regeneration after injury. In this study, we investigated the role of amyloid precursor protein (APP) and its paralogue amyloid precursor-like protein 2 (APLP2) in myelination using APP and APLP2 knockout (KO) mice. Given that BACE1 regulates myelination and myelin sheath thickness in both the peripheral and central nervous systems, we sought to determine if APP and APLP2, as alternate BACE1 substrates, also modulate myelination, and therefore provide a better understanding of the events regulating axonal myelination. In the peripheral nervous system, we identified that adult, but not juvenile KO mice, have lower densities of myelinated axons in their sciatic nerves while in the central nervous system, axons within both the optic nerves and corpus callosum of both KO mice were significantly hypomyelinated compared to wild-type (WT) controls. Biochemical analysis demonstrated significant increases in BACE1 and myelin oligodendrocyte glycoprotein and decreased NRG1 and proteolipid protein levels in both KO brain tissue. The acute cuprizone model of demyelination/remyelination revealed that whereas axons in the corpus callosum of WT and APLP2-KO mice underwent similar degrees of demyelination and subsequent remyelination, the myelinated callosal axons in APP-KO mice were less susceptible to cuprizone-induced demyelination and showed a failure in remyelination after cuprizone withdrawal. These data identified APP and APLP2 as modulators of normal myelination and demyelination/remyelination conditions. Deletion of APP and APLP2 identifies novel interplays between the BACE1 substrates in the regulation of myelination