MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system

Background  

MicroRNA (miRNA) encoding genes are abundant in vertebrate genomes but very few have been studied in any detail. Bioinformatic tools allow prediction of miRNA targets and this information coupled with knowledge of miRNA expression profiles facilitates formulation of hypotheses of miRNA function. Although the central nervous system (CNS) is a prominent site of miRNA expression, virtually nothing is known about the spatial and temporal expression profiles of miRNAs in the brain. To provide an overview of the breadth of miRNA expression in the CNS, we performed a comprehensive analysis of the neuroanatomical expression profiles of 38 abundant conserved miRNAs in developing and adult zebrafish brain.     

Candida albicans SET1 encodes a histone 3 lysine 4 methyltransferase that contributes to the pathogenesis of invasive candidiasis

Candida albicans causes diverse mucosal and systemic diseases. Although this versatility likely depends upon carefully co-ordinated gene expression, epigenetic regulation in C. albicans remains poorly characterized. Screening a genomic expression library, we identified C. albicans Set1p as an immunogenic protein with homology to a lysine histone methyltransferase of Saccharomyces cerevisiae. In this study, we demonstrated that total immunoglobulin, IgG and IgM titers against a unique Set1p N-terminal fragment were significantly higher among patients with disseminated candidiasis (DC) or oropharyngeal candidiasis than controls. Disruption of SET1 resulted in complete loss of methylation of histone 3 at lysine residue 4, hyperfilamentous growth under embedded conditions, less negative cell surface charges and diminished adherence to epithelial cells, effects that were reversed upon gene re-insertion at a disrupted locus. During murine DC, the null mutant was associated with prolonged survival and lower tissue burdens. Taken together, our findings suggest that SET1 regulates multiple processes important to the pathogenesis of candidiasis. The Set1p N-terminal fragment does not exhibit significant homology to eukaryotic or microbial proteins, and might represent a novel therapeutic, preventive or diagnostic target.     

A Highlights from MBoC Selection: Unregulated ARF6 Activation in Epithelial Cysts Generates Hyperactive Signaling Endosomes and Disrupts Morphogenesis

Tumor development in glandular tissues is associated with structural alterations in the hollow ducts and spherical structures that comprise such tissues. We describe a signaling axis involving sustained activation of the GTP-binding protein, ARF6, that provokes dramatic changes in the organization of epithelial cysts, reminiscent of tumorigenic glandular phenotypes. In reconstituted basement membrane cultures of renal epithelial cysts, enhanced ARF6 activation induces the formation of cell-filled glandular structures with multiple lumens and disassembled cadherin-based cell–cell contacts. All of these alterations are accompanied by growth factor receptor internalization into signaling endosomes and reversed by blocking ARF6 activation or receptor endocytosis. Receptor localization in signaling endosomes results in hyperactive extracellular signal-regulated kinase signaling leading to Bcl-2 stabilization and aberrant cysts. Similarly, formation of hyperproliferative and disorganized mammary acini induced by chronic stimulation of colony-stimulating factor 1 receptor is coupled to endogenous ARF6 activation and constitutive receptor internalization and is reversed by ARF6 inhibition. These findings identify a previously unrecognized link between ARF6-regulated receptor internalization and events that drive dramatic alterations in cyst morphogenesis providing new mechanistic insight into the molecular processes that can promote epithelial glandular disruption.     

Determinants of heterogeneity, excitation and conduction in the sinoatrial node: a model study

The sinoatrial node (SAN) is a complex structure that exhibits anatomical and functional heterogeneity which may depend on: 1) The existence of distinct cell populations, 2) electrotonic influences of the surrounding atrium, 3) the presence of a high density of fibroblasts, and 4) atrial cells intermingled within the SAN. Our goal was to utilize a computer model to predict critical determinants and modulators of excitation and conduction in the SAN. We built a theoretical "non-uniform" model composed of distinct central and peripheral SAN cells and a "uniform" model containing only central cells connected to the atrium. We tested the effects of coupling strength between SAN cells in the models, as well as the effects of fibroblasts and interspersed atrial cells. Although we could simulate single cell experimental data supporting the "multiple cell type" hypothesis, 2D "non-uniform" models did not simulate expected tissue behavior, such as central pacemaking. When we considered the atrial effects alone in a simple homogeneous "uniform" model, central pacemaking initiation and impulse propagation in simulations were consistent with experiments. Introduction of fibroblasts in our simulated tissue resulted in various effects depending on the density, distribution, and fibroblast-myocyte coupling strength. Incorporation of atrial cells in our simulated SAN tissue had little effect on SAN electrophysiology. Our tissue model simulations suggest atrial electrotonic effects as plausible to account for SAN heterogeneity, sequence, and rate of propagation. Fibroblasts can act as obstacles, current sinks or shunts to conduction in the SAN depending on their orientation, density, and coupling.