The role for inhibitory Fc gamma receptors class IIb (FcgammaRIIb) in the onset, progression and severity of several animal models of autoimmune diseases is well established. By contrast, the pathogenic potential of FcgammaRIIb in human autoimmune diseases remains largely unknown. Here we report the identification of a polymorphism in the human FCGR2B promoter (dbSNP no. rs3219018) that is associated in homozygosity with systemic lupus erythematosus (SLE) phenotype in European-Americans (OR=11.1, P=0.003). Experimental evidence correlates the polymorphism (a G-C substitution at position -343 relative to the start of transcription) with altered FcgammaRIIb expression and function. The G-C substitution correlated with decreased transcription of the FCGR2B promoter, and resulted in decreased binding of the AP1 transcription complex to the mutant promoter sequence. The surface expression of FcgammaRIIb receptors was significantly reduced in activated B cells from (-343 C/C) SLE patients. These findings suggest that genetic defects may lead to deregulated expression of the FCGR2B gene in -343 C/C homozygous subjects, and may play a role in the pathogenesis of human SLE.
Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.
SUMMARYHeterozygous deletions encompassing the ZIC1;ZIC4 locus have been identified in a subset of individuals with the common cerebellar birth defect Dandy-Walker malformation (DWM). Deletion of Zic1 and Zic4 in mice produces both cerebellar size and foliation defects similar to human DWM, confirming a requirement for these genes in cerebellar development and providing a model to delineate the developmental basis of this clinically important congenital malformation. Here, we show that reduced cerebellar size in Zic1 and Zic4 mutants results from decreased postnatal granule cell progenitor proliferation. , we observed normal cerebellar anlage patterning and foliation. Furthermore, cerebellar patterning was normal in both Gli2-cko and Smo-cko mutant mice, where all Shh function was removed from the developing cerebellum. Thus, our data demonstrate that Zic1 and Zic4 have both Shh-dependent and -independent roles during cerebellar development and that multiple developmental disruptions underlie Zic1/4-related DWM.
Receptors for IgG (FcγR) expressed in dendritic cells (DCs) influence the initiation of Ab-mediated immunity. Dynamic variations in FcγR expression allow DCs to adjust their capacity to capture Ab-opsonized Ag. The current paradigm predicts a progressive decline in FcγR-mediated phagocytic function upon DC maturation. Surprisingly, we find that expression of the phagocytic receptor FcγRIIa is preserved in immature and mature DCs at comparable levels with macrophages. Moreover, phagocytosis of antigenic peptides directed to FcγRIIa on DCs leads to dramatic increases in Ag cross-presentation and T cell activation. In immature DCs, high expression of inhibitory FcγRIIb correlates with decreased uptake and cross-presentation of Ab-Ag complexes. In contrast, engagement of FcγRIIb is not associated with changes in cross-presentation in mature DCs. We provide evidence that FcγRIIb expression is patently reduced in mature DCs, an effect that is modulated by treatment with cytokines. The regulated expression of activating and inhibitory FcγRs in DCs emerges as a critical checkpoint in the process of Ag uptake and cross-presentation
Primary sensory nuclei of the thalamus process and relay parallel channels of sensory input into the cortex. The developmental processes by which these nuclei acquire distinct functional roles are not well understood. To identify novel groups of genes with a potential role in differentiating two adjacent sensory nuclei, we performed a microarray screen comparing perinatal gene expression in the principal auditory relay nucleus, the medial geniculate nucleus (MGN), and principal visual relay nucleus, the lateral geniculate nucleus (LGN). We discovered and confirmed groups of highly ranked, differentially expressed genes with qRT-PCR and in situ hybridization. A functional role for Zic4, a transcription factor highly enriched in the LGN, was investigated using Zic4-null mice, which were found to have changes in topographic patterning of retinogeniculate projections. Foxp2, a transcriptional repressor expressed strongly in the MGN, was found to be positively regulated by activity in the MGN. These findings identify roles for two differentially expressed genes, Zic4 and Foxp2, in visual and auditory pathway development. Finally, to test whether modality-specific patterns of gene expression are influenced by extrinsic patterns of input, we performed an additional microarray screen comparing the normal MGN to “rewired” MGN, in which normal auditory afferents are ablated and novel retinal inputs innervate the MGN. Data from this screen indicate that rewired MGN acquires some patterns of gene expression that are present in the developing LGN, including an upregulation of Zic4 expression, as well as novel patterns of expression which may represent unique processes of cross-modal plasticity.
Fc gamma receptors (Fc gammaR) trigger inflammatory reactions in response to immunoglobulin-opsonized pathogens and antigen-antibody complexes. The coordinate expression of activating and inhibitory Fc gammaR ensures the homeostasis of immune complex-driven inflammatory responses. In this study, we used antibodies with preferential binding for activating Fc gammaRIIa and inhibitory Fc gammaRIIb receptors to investigate the expression and regulation of Fc gammaRII isoforms in human monocytes. Cross-linking of Fc gammaRIIa triggered phagocytosis and cytokine production. Cross-linking of Fc gammaRIIb was associated with phosphorylation of the immunoreceptor tyrosine-based inhibitory motif and with a marked reduction in monocyte effector functions. Our study revealed that tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-10, and IL-13 altered the transcriptional activity of the Fc gammaRIIB promoter in transfected cell lines and skewed the balance of activating versus inhibitory Fc gammaR in human monocytes. TNF-alpha decreased the expression of inhibitory Fc gammaRIIb. IL-10 up-regulated all classes of Fc gammaR and induced alternative activation in monocytes, an effect that was synergistic with that of TNF-alpha. In contrast, IL-4 and IL-13, in combination with TNF-alpha, decreased the expression of activating Fc gammaR and markedly down-regulated Fc gammaR-mediated function. Our findings suggest that the cytokine milieu can induce changes in the relative expression of Fc gammaR with opposing function and thus, may regulate the amplitude of Fc gammaR-mediated uptake and inflammation.
The inhibitory receptor Fc␥RIIb is a negative regulator of antibody production and inflammatory responses. The ؊343 G 3 C polymorphism in the human FCGR2B promoter is associated with systemic lupus erythematosus. The ؊343 C mutant promoter has decreased transcriptional activity. In the present study, we show that the transcriptional change correlates with quantitative differences in the interaction of the activating protein 1 complex with the mutant FCGR2B promoter. Promoter pulldown and chromatin immunoprecipitation assays demonstrated binding of c-Jun to the FCGR2B promoter. Phosphorylation of c-Jun was accompanied by transactivation of both FCGR2B promoter variants, whereas dephosphorylation of c-Jun by an inhibitor of c-Jun N-terminal kinase, markedly decreased the promoter activities. The ؊343 G 3 C substitution enabled the specific interaction of the transcription factor YinYang 1 with the mutant FCGR2B promoter. Yin-Yang 1 competed with activating protein 1 for binding at the ؊343 site, and contributed to the repression of the mutant FCGR2B promoter activity. This mechanism could be responsible for the decreased expression of Fc␥RIIb associated with the ؊343 C/C homozygous FCGR2B genotype in lupus patients. These findings provide a rationale for the transcriptional defect mediated by the ؊343 C/C FCGR2B promoter polymorphism associated with systemic lupus erythematosus, and add to our understanding of the complex transcriptional regulation of the human FCGR2B promoter.Fc ␥-receptors (Fc␥R) 2 bind IgG-containing immune complexes and mediate important immune functions such as phagocytosis, degranulation, antibody-dependent cellular cytotoxicity, and production of inflammatory mediators. Human hematopoetic cells express several Fc␥R isoforms encoded by seven separate genes. Unlike activating Fc␥R, Fc␥RIIb is unique in that it contains an immunoreceptor tyrosine-based inhibitory motif in the intracellular domain. A specific amino acid sequence in the immunoreceptor tyrosine-based inhibitory motif domain of Fc␥RIIb allows the recruitment of phosphatases and the initiation of inhibitory signaling. Cross-linking of Fc␥RIIb with activating receptors on B cells and mononuclear phagocytes leads to down-regulation of antibody production, phagocytosis, and cytokine secretion. Several lines of evidence demonstrate that Fc␥RIIb is important in the maintenance of self-tolerance. Fc␥RIIb deficiency is associated with spontaneous development of autoimmune manifestations in several mouse genetic backgrounds (1). Autoimmune prone mouse strains share an Fcgr2 promoter haplotype containing deletions and polymorphisms associated with reduced expression of Fc␥RIIb on the surface of activated B cells and macrophages (2-4). Whereas the engineered deletion and the natural deficiency in Fc␥RIIb confer susceptibility to development of lupus-like disease, transplantation of bone marrow cells transduced with Fc␥RIIb-expressing retrovirus restored the healthy phenotype (5). This body of data created the impetus for the study of Fc␥RIIb...
KJ. If the skull fits: magnetic resonance imaging and microcomputed tomography for combined analysis of brain and skull phenotypes in the mouse. Physiol Genomics 44: 992-1002. First published September 4, 2012 doi:10.1152/physiolgenomics.00093.2012.-The mammalian brain and skull develop concurrently in a coordinated manner, consistently producing a brain and skull that fit tightly together. It is common that abnormalities in one are associated with related abnormalities in the other. However, this is not always the case. A complete characterization of the relationship between brain and skull phenotypes is necessary to understand the mechanisms that cause them to be coordinated or divergent and to provide perspective on the potential diagnostic or prognostic significance of brain and skull phenotypes. We demonstrate the combined use of magnetic resonance imaging and microcomputed tomography for analysis of brain and skull phenotypes in the mouse. Co-registration of brain and skull images allows comparison of the relationship between phenotypes in the brain and those in the skull. We observe a close fit between the brain and skull of two genetic mouse models that both show abnormal brain and skull phenotypes. Application of these three-dimensional image analyses in a broader range of mouse mutants will provide a map of the relationships between brain and skull phenotypes generally and allow characterization of patterns of similarities and differences. craniofacial development; mouse phenotyping; mouse imaging; oculodentodigital dysplasia; Dandy-Walker malformation THE DEVELOPMENT OF THE BRAIN and skull is an intricate and coordinated process that results in two complex structures fitting tightly together. Both physical and genetic factors participate in the direction of this process, and changes in either may result in an altered brain and/or skull morphometry. Characterization of such alterations, and of how brain and skull alterations relate to one another, will provide insight into the process of normal brain and skull development and into conditions where this development is perturbed.It is recognized that the physical interaction between structures in the developing brain and skull can induce covariation in their shape (61). Premature fusion of a cranial suture, for example, results in an abnormal skull shape due to growth restriction in one direction (51). Brain growth is also physically constrained in these circumstances, and the brain is similarly altered in shape (5,6,77). Fear of increased intracranial pressure and abnormal craniofacial development motivates corrective surgery in these patients to partly normalize anatomical outcome (71). Furthermore, simple geometric measurements of the skull, such as the angle between the skull base and the front of the brain or landmarks on the facial bones, show a high degree of correlation with the total volume of the brain (16,59,81,82). This observation seems to hold true in multiple species of mammals, a fact that informs some studies in anthropology and evoluti...
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