The Hippo signaling pathway is required for salivary gland development and its dysregulation is associated with Sjogren's-like disease

Sjogren's syndrome (SS) is a complex autoimmune disease that primarily affects salivary and lacrimal glands and is associated with high morbidity. Although the prevailing dogma is that immune system pathology drives SS, increasing evidence points to structural defects, including defective E-cadherin adhesion, to be involved in its etiology. We have shown that E-cadherin plays pivotal roles in the development of the mouse salivary submandibular gland (SMG) by organizing apical-basal polarity in acinar and ductal progenitors and by signaling survival for differentiating duct cells. Recently, E-cadherin junctions have been shown to interact with effectors of the Hippo signaling pathway, a core pathway regulating organ size, cell proliferation and differentiation. We now show that Hippo signaling is required for SMG branching morphogenesis and is involved in the pathophysiology of SS. During SMG development, a Hippo pathway effector, TAZ, becomes increasingly phosphorylated and associated with E-cadherin and α-catenin, consistent with the activation of Hippo signaling. Inhibition of Lats2, an upstream kinase that promotes TAZ phosphorylation, results in dysmorphogenesis of the SMG and impaired duct formation. SMGs from NOD mice, a mouse model for SS, phenocopy the Lats2-inhibited SMGs and exhibit a reduction in E-cadherin junctional components, including TAZ. Importantly, labial specimens from human SS patients display mislocalization of TAZ from junctional regions to the nucleus, coincident with accumulation of extracellular matrix components, fibronectin and CTGF, known downstream targets of TAZ. Our studies show that Hippo signaling plays a crucial role in SMG branching morphogenesis and provide evidence that defects in this pathway are associated with SS in humans

Specification of the patterning of a ductal tree during branching morphogenesis of the submandibular gland.

The development of ductal structures during branching morphogenesis relies on signals that specify ductal progenitors to set up a pattern for the ductal network. Here, we identify cellular asymmetries defined by the F-actin cytoskeleton and the cell adhesion protein ZO-1 as the earliest determinants of duct specification in the embryonic submandibular gland (SMG). Apical polarity protein aPKCζ is then recruited to the sites of asymmetry in a ZO-1-dependent manner and collaborates with ROCK signaling to set up apical-basal polarity of ductal progenitors and further define the path of duct specification. Moreover, the motor protein myosin IIB, a mediator of mechanical force transmission along actin filaments, becomes localized to vertices linking the apical domains of multiple ductal epithelial cells during the formation of ductal lumens and drives duct maturation. These studies identify cytoskeletal, junctional and polarity proteins as the early determinants of duct specification and the patterning of a ductal tree during branching morphogenesis of the SMG

cPath: open source software for collecting, storing, and querying biological pathways

BACKGROUND: Biological pathways, including metabolic pathways, protein interaction networks, signal transduction pathways, and gene regulatory networks, are currently represented in over 220 diverse databases. These data are crucial for the study of specific biological processes, including human diseases. Standard exchange formats for pathway information, such as BioPAX, CellML, SBML and PSI-MI, enable convenient collection of this data for biological research, but mechanisms for common storage and communication are required. RESULTS: We have developed cPath, an open source database and web application for collecting, storing, and querying biological pathway data. cPath makes it easy to aggregate custom pathway data sets available in standard exchange formats from multiple databases, present pathway data to biologists via a customizable web interface, and export pathway data via a web service to third-party software, such as Cytoscape, for visualization and analysis. cPath is software only, and does not include new pathway information. Key features include: a built-in identifier mapping service for linking identical interactors and linking to external resources; built-in support for PSI-MI and BioPAX standard pathway exchange formats; a web service interface for searching and retrieving pathway data sets; and thorough documentation. The cPath software is freely available under the LGPL open source license for academic and commercial use. CONCLUSION: cPath is a robust, scalable, modular, professional-grade software platform for collecting, storing, and querying biological pathways. It can serve as the core data handling component in information systems for pathway visualization, analysis and modeling

MicroRNAs:New players in IBD

MicroRNAs (miRNAs) are small non-coding RNAs, 18–23 nucleotides long, which act as post-transcriptional regulators of gene expression. miRNAs are strongly implicated in the pathogenesis of many common diseases, including IBDs. This review aims to outline the history, biogenesis and regulation of miRNAs. The role of miRNAs in the development and regulation of the innate and adaptive immune system is discussed, with a particular focus on mechanisms pertinent to IBD and the potential translational applications