- Brain homeostasis: VEGF receptor 1 and 2 - two unequal brothers in mind (2013)
- Vascular endothelial growth factors (VEGFs), initially thought to act specifically on the vascular system, exert trophic effects on neural cells during development and adulthood. Therefore, the VEGF system serves as a promising therapeutic target for brain pathologies, but its simultaneous action on vascular cells paves the way for harmful side effects. To circumvent these deleterious effects, many studies have aimed to clarify whether VEGFs directly affect neural cells or if the effects are mediated secondarily via other cell types, like vascular cells. A great number of reports have shown the expression and function of VEGF receptors (VEGFRs), mainly VEGFR-1 and -2, in neural cells, where VEGFR-2 has been described as the major mediator of VEGF-A signals. This review aims to summarize and compare the divergent roles of VEGFR-1 and -2 during CNS development and homeostasis.
- Cell specific crosstalk of the Wnt/β-catenin and the Shh pathway: implications for tumor development and regression (2011)
- The canonical Wnt/β-catenin and the Shh pathway as well as the Notch signaling cascade are key regulators in stem cell biology and are independently associated with the development of cancer. Despite the knowledge of a balanced signaling for cellular maintenance, the fundamental biochemical mechanisms of crosstalk are still poorly understood. This study demonstrates that the outcome of interaction between Wnt and Shh is cell type specific. A combined inhibitory mechanism of the Shh and Notch2/Jagged2 pathways on dominant active β-catenin signaling in the adult tongue epithelium keeps Wnt/β-catenin signaling restricted to physiological tolerable levels. In the opposite crosstalk the activation of Wnt/β-catenin signaling in medulloblastoma (MB) of the Shh subtype, in turn inhibits the Hh pathway. The inhibitory mechanism of Shh and Notch2/Jagged2 on Wnt/β-catenin signaling is independent of the degradation complex of β-catenin and takes place inside the nucleus. Furthermore, the negative feedback on Wnt/β-catenin signaling by the Shh pathway relies on transcriptional activity of Gli1/2A. Inhibition of Gli1/2A with the specific inhibitor GANT61 abrogated the negative impact of Shh on β-catenin signaling in vitro. Although the negative feedback loop of Shh is still functional in human SCC25 cells, the inhibitory effect of Notch2/Jagged2 is lost and contributes to the cancerogenic phenotype of these cells. In the inverse situation, the activation of β−catenin signaling has a negative feedback on constantly active Shh signaling and significantly inhibits the Hh pathway. This was shown in Ptch+/- and Math1-Cre:SmoM2Fl/+ MB tumor spheres in vitro, in which inhibition of sphere formation and growth was observed and Hh target gene transcription was down-regulated. This demonstrates for the first time that the activation of canonical Wnt/β-catenin signaling in primary MB cells with a Hh pathway over-activation has a negative effect on the growth of these cells in vitro. In summary the results show that crosstalk of Wnt/β-catenin and Shh signaling has context specific outcome on pathway activity. Elucidation of the molecular interactions will improve our understanding of Wnt and Hh associated tumors and contribute to the development of new therapeutic strategies.
- Single-particle characterization of ice-nucleating particles and ice particles residuals sampled by three different techniques (2015)
- During January/February 2013, at the High Alpine Research Station Jungfraujoch a measurement campaign was carried out, which was centered on atmospheric ice-nucleating particles (INP) and ice particle residuals (IPR). Three different techniques for separation of INP and IPR from the non-ice-active particles are compared. The Ice Selective Inlet (ISI) and the Ice Counterflow Virtual Impactor (Ice-CVI) sample ice particles from mixed phase clouds and allow for the analysis of the residuals. The combination of the Fast Ice Nucleus Chamber (FINCH) and the Ice Nuclei Pumped Counterflow Virtual Impactor (IN-PCVI) provides ice-activating conditions to aerosol particles and extracts the activated INP for analysis.Collected particles were analyzed by scanning electron microscopy and energy-dispersive X-ray microanalysis to determine size, chemical composition and mixing state. All INP/IPR-separating techniques had considerable abundances (median 20 – 70 %) of instrumental contamination artifacts (ISI: Si-O spheres, probably calibration aerosol; Ice-CVI: Al-O particles; FINCH+IN-PCVI: steel particles). Also, potential sampling artifacts (e.g., pure soluble material) occurred with a median abundance of < 20 %. While these could be explained as IPR by ice break-up, for INP their IN-ability pathway is less clear. After removal of the contamination artifacts, silicates and Ca-rich particles, carbonaceous material and metal oxides were the major INP/IPR particle types separated by all three techniques. Soot was a minor contributor. Lead was detected in less than 10 % of the particles, of which the majority were internal mixtures with other particle types. Sea-salt and sulfates were identified by all three methods as INP/IPR. Most samples showed a maximum of the INP/IPR size distribution at 400 nm geometric diameter. In a few cases, a second super-micron maximum was identified. Soot/carbonaceous material and metal oxides were present mainly in the submicron range. ISI and FINCH yielded silicates and Ca-rich particles mainly with diameters above 1 μm, while the Ice-CVI also separated many submicron IPR. As strictly parallel sampling could not be performed, a part of the discrepancies between the different techniques may result from variations in meteorological conditions and subsequent INP/IPR composition. The observed differences in the particle group abundances as well as in the mixing state of INP/IPR express the need for further studies to better understand the influence of the separating techniques on the INP/IPR chemical composition.