Point Mutations in GLI3 Lead to Misregulation of its Subcellular Localization

Background Mutations in the transcription factor GLI3, a downstream target of Sonic Hedgehog (SHH) signaling, are responsible for the development of malformation syndromes such as Greig-cephalopolysyndactyly-syndrome (GCPS), or Pallister-Hall-syndrome (PHS). Mutations that lead to loss of function of the protein and to haploinsufficiency cause GCPS, while truncating mutations that result in constitutive repressor function of GLI3 lead to PHS. As an exception, some point mutations in the C-terminal part of GLI3 observed in GCPS patients have so far not been linked to loss of function. We have shown recently that protein phosphatase 2A (PP2A) regulates the nuclear localization and transcriptional activity a of GLI3 function. Principal Findings We have shown recently that protein phosphatase 2A (PP2A) and the ubiquitin ligase MID1 regulate the nuclear localization and transcriptional activity of GLI3. Here we show mapping of the functional interaction between the MID1-α4-PP2A complex and GLI3 to a region between amino acid 568-1100 of GLI3. Furthermore we demonstrate that GCPS-associated point mutations, that are located in that region, lead to misregulation of the nuclear GLI3-localization and transcriptional activity. GLI3 phosphorylation itself however appears independent of its localization and remains untouched by either of the point mutations and by PP2A-activity, which suggests involvement of an as yet unknown GLI3 interaction partner, the phosphorylation status of which is regulated by PP2A activity, in the control of GLI3 subcellular localization and activity. Conclusions The present findings provide an explanation for the pathogenesis of GCPS in patients carrying C-terminal point mutations, and close the gap in our understanding of how GLI3-genotypes give rise to particular phenotypes. Furthermore, they provide a molecular explanation for the phenotypic overlap between Opitz syndrome patients with dysregulated PP2A-activity and syndromes caused by GLI3-mutations

The chemokine receptor CXCR5 is pivotal for ectopic mucosa-associated lymphoid tissue neogenesis in chronic Helicobacter pylori-induced inflammation

Ectopic lymphoid follicles are a key feature of chronic inflammatory autoimmune and infectious diseases, such as rheumatoid arthritis, Sjögren's syndrome, and Helicobacter pylori-induced gastritis. Homeostatic chemokines are considered to be involved in the formation of such tertiary lymphoid tissue. High expression of CXCL13 and its receptor, CXCR5, has been associated with the formation of ectopic lymphoid follicles in chronic infectious diseases. Here, we defined the role of CXCR5 in the development of mucosal tertiary lymphoid tissue and gastric inflammation in a mouse model of chronic H. pylori infection. CXCR5-deficient mice failed to develop organized gastric lymphoid follicles despite similar bacterial colonization density as infected wild-type mice. CXCR5 deficiency altered Th17 responses but not Th1-type cellular immune responses to H. pylori infection. Furthermore, CXCR5-deficient mice exhibited lower H. pylori-specific serum IgG and IgA levels and an overall decrease in chronic gastric immune responses. In conclusion, the development of mucosal tertiary ectopic follicles during chronic H. pylori infection is strongly dependent on the CXCL13/CXCR5 signaling axis, and lack of de novo lymphoid tissue formation attenuates chronic immune responses

Reply to Nielsen et al. social mindfulness is associated with countries’ environmental performance and individual environmental concern

info:eu-repo/semantics/publishedVersio

From local social mindfulness to global sustainability efforts?

info:eu-repo/semantics/publishedVersio

Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits

Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability

Social mindfulness and prosociality vary across the globe

Humans are social animals, but not everyone will be mindful of others to the same extent. Individual differences have been found, but would social mindfulness also be shaped by one’s location in the world? Expecting cross-national differences to exist, we examined if and how social mindfulness differs across countries. At little to no material cost, social mindfulness typically entails small acts of attention or kindness. Even though fairly common, such low-cost cooperation has received little empirical attention. Measuring social mindfulness across 31 samples from industrialized countries and regions (n = 8,354), we found considerable variation. Among selected country-level variables, greater social mindfulness was most strongly associated with countries’ better general performance on environmental protection. Together, our findings contribute to the literature on prosociality by targeting the kind of everyday cooperation that is more focused on communicating benevolence than on providing material benefits

Funktionale Bedeutung der homöostatischen Chemokinrezeptoren CCR7 und CXCR5 im Verlauf von mukosalen Immunantworten

Die kontinuierliche Rezirkulation von Immunzellen durch periphere und sekundäre lymphatische Organe (SLOs) ist Bestandteil der Immunüberwachung und wichtig für die Aufrechterhaltung und Funktionsbereitschaft des Immunsystems. Der homöostatische Chemokinrezeptor CCR7 vermittelt dabei nicht nur die Rezirkulation von Lymphozyten durch SLOs, sondern scheint auch an der homöostatischen Rezirkulation von Lymphozyten durch nicht-lymphoide periphere Gewebe beteiligt zu sein. Im Rahmen dieser Arbeit wurde mithilfe von CCR7-defizienten Mäusen die funktionale Bedeutung von CCR7 für die homöostatische Rezirkulation von Lymphozyten durch das Peritoneum untersucht und nachgewiesen, dass CCR7 der dominante Chemokinrezeptor ist, der unter physiologischen Bedingungen die Transitzeit von Lymphozyten durch das Peritoneum festlegt. Die gestörte Rezirkulation von Lymphozyten begünstigte außerdem die Entstehung von tertiären lymphoiden Organen (TLOs) in der Magenschleimhaut von CCR7-defizienten Mäusen. Untersuchungen zur zellulären und molekularen Grundlage dieser und weiterer pathomorphologischer Veränderungen in der Magenschleimhaut von CCR7-defizienten Mäusen verdeutlichten die Funktion von CCR7 für die Etablierung von zentraler und peripherer Toleranz gegenüber gastrischen Antigenen. Fehlt CCR7, dann entwickelten Mäuse eine spontane Autoimmungastritis, welche durch gastritogene CD4+ T-Zellen verursacht wurde, deren Aktivierung auch unabhängig von Lymphknoten und TLOs erfolgte. Die Entstehung von TLOs wird auch bei einer durch Helicobacter pylori ausgelösten chronischen Gastritis beobachtet. Die Expression des homöostatischen Chemokinrezeptors CXCR5 und seines Liganden CXCL13 ist mit der Entwicklung dieser TLOs korreliert worden. Unter Verwendung eines Mausmodells für H. pylori-induzierte chronische Gastritis konnte gezeigt werden, dass CXCR5 die Ausbildung von TLOs vermittelt und eine Rolle für die Induktion von H. pylori-spezifischen T-Zell- sowie humoralen Immunantworten spielt.Homeostatic recirculation of immune cells through peripheral and secondary lympoid organs (SLOs) is required for immune surveillance and the maintenance and functionality of the immune system. The homeostatic chemokine receptor CCR7 controls not only lymphoid cell trafficking to and within SLOs, but also seems to be involved in the homeostatic recirculation of lymphocytes through non-lymphoid peripheral tissues. Within the scope of this work we investigated the functional relevance of CCR7 for the homeostatic recirculation of lymphocytes through the peritoneal cavity and could show, that CCR7 is the dominant chemokine receptor which defines the transit time of lymphocytes in the peritoneal cavity under physiological conditions. Impaired recirculation of lymphocytes also promoted the development of tertiary lymphoid organs (TLOs) in the gastric mucosa of CCR7-deficient mice. Analysis of the cellular and molecular mechanisms underlying these and other pathomorphological alterations in the gastric mucosa of CCR7-deficient mice provided further evidence regarding the function of CCR7 for the establishment of central and peripheral tolerance towards gastric antigens. Mice that lack CCR7 spontaneously developed autoimmune gastritis, which was caused by gastritogenic CD4+ T-cells. Such autoreactive T cell responses were also initiated in the absence of lymph nodes and TLOs in CCR7/LT-alpha double-deficient mice. Development of TLOs is also observed during chronic gastritis induced by Helicobacter pylori. The expression of the homeostatic chemokine receptor CXCR5 and its ligand CXCL13 has been correlated with the development of these TLOs. Using a mouse model for H. pylori-induced chronic gastritis, we could show that CXCR5 is responsible for the development of TLOs and also plays a role for the induction of H. pylori-specific T and B cell responses

Alternative polyadenylation signals and promoters act in concert to control tissue-specific expression of the Opitz syndrome gene MID1

<p>Abstract</p> <p>Background</p> <p>Mutations in the X-linked <it>MID1 </it>gene are responsible for Opitz G/BBB syndrome, a malformation disorder of developing midline structures. Previous Northern blot analyses revealed the existence of at least three <it>MID1 </it>transcripts of differing lengths.</p> <p>Results</p> <p>Here we show that alternative polyadenylation generates the size differences observed in the Northern blot analyses. Analysis of EST data together with additional Northern blot analyses proved tissue-specific usage of the alternative polyadenylation sites. Bioinformatic characterization of the different 3'UTRs of <it>MID1 </it>revealed numerous RNA-protein interaction motifs, several of which turned out to be conserved between different species. Furthermore, our data suggest that mRNA termination at different polyadenylation sites is predetermined by the choice of alternative 5'UTRs and promoters of the <it>MID1 </it>gene, a mechanism that efficiently allows synergistic function of 5' and 3'UTRs.</p> <p>Conclusion</p> <p><it>MID1 </it>expression is tightly regulated through concerted action of alternative promoters and alternative polyadenylation signals both during embryonic development and in the adult.</p