Slit-Robo signalling establishes a Sphingosine-1-phosphate gradient to polarise fin mesenchyme.

Immigration of mesenchymal cells into the growing fin and limb buds drives distal outgrowth, with subsequent tensile forces between these cells essential for fin and limb morphogenesis. Morphogens derived from the apical domain of the fin, orientate limb mesenchyme cell polarity, migration, division and adhesion. The zebrafish mutant stomp displays defects in fin morphogenesis including blister formation and associated loss of orientation and adhesion of immigrating fin mesenchyme cells. Positional cloning of stomp identifies a mutation in the gene encoding the axon guidance ligand, Slit3. We provide evidence that Slit ligands derived from immigrating mesenchyme act via Robo receptors at the apical ectodermal ridge (AER) to promote release of sphingosine-1-phosphate (S1P). S1P subsequently diffuses back to the mesenchyme to promote their polarisation, orientation, positioning and adhesion to the interstitial matrix of the fin fold. We thus demonstrate the coordination of the Slit-Robo and S1P signalling pathways in fin fold morphogenesis. Our work introduces a mechanism regulating the orientation, positioning and adhesion of its constituent cells.

Advances in understanding the pathogenesis of Barrett's esophagus.

Barrett's esophagus (BE) is an intestinal-like columnar metaplasia that replaces the normal stratified squamous epithelium in the distal esophagus. Clinically, BE is an important entity as it is the only established precursor to esophageal adenocarcinoma (EAC), a disease with an extremely poor prognosis and an incidence that is rising faster than any other solid cancer worldwide. Therefore, because of the increasing burden of EAC, there has been much research aimed at understanding the development of BE, in order to develop new ways to combat this disease. BE arises as a consequence of chronic reflux. Whilst the central role of reflux in driving the development of BE has been well established, the cellular and molecular mechanisms that accompany this process remain to be fully elucidated. Understanding the drivers at a fundamental level is crucial for the rational design of novel therapeutic strategies aimed at preventing the progression of, or even reversing, BE. In this article we review some of the recent advances that have contributed to our understanding of BE pathogenesis, including new findings on the possible cellular origins of the metaplastic epithelium, and the morphogens and transcription factors that putatively drive the conversion of the squamous epithelium to an intestinal-like columnar epithelium.

Translational research on Barrett's esophagus.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on translational research on Barrett's esophagus that address evidence for genetic instability in esophageal cancer; the role of microsatellite instability; the use of histologic and serum Doublecortin-like kinase 1 expression for progression of Barrett's esophagus to adenocarcinoma; the oxidative stress in Barrett's tumorigenesis; the genomic alterations in esophageal cancer; in vivo modeling in Barrett's esophagus; epigenetic and transcriptional regulation in Barrett's esophagus and esophageal adenocarcinoma; and normal and disordered regeneration in Barrett's esophagus.

Integrative genomic, transcriptional, and proteomic diversity in natural isolates of the human pathogen Burkholderia pseudomallei.

Natural isolates of pathogenic bacteria can exhibit a broad range of phenotypic traits. To investigate the molecular mechanisms contributing to such phenotypic variability, we compared the genomes, transcriptomes, and proteomes of two natural isolates of the gram-negative bacterium Burkholderia pseudomallei, the causative agent of the human disease melioidosis. Significant intrinsic genomic, transcriptional, and proteomic variations were observed between the two strains involving genes of diverse functions. We identified 16 strain-specific regions in the B. pseudomallei K96243 reference genome, and for eight regions their differential presence could be ascribed to either DNA acquisition or loss. A remarkable 43% of the transcriptional differences between the strains could be attributed to genes that were differentially present between K96243 and Bp15682, demonstrating the importance of lateral gene transfer or gene loss events in contributing to pathogen diversity at the gene expression level. Proteins expressed in a strain-specific manner were similarly correlated at the gene expression level, but up to 38% of the global proteomic variation between strains comprised proteins expressed in both strains but associated with strain-specific protein isoforms. Collectively, >65 hypothetical genes were transcriptionally or proteomically expressed, supporting their bona fide biological presence. Our results provide, for the first time, an integrated framework for classifying the repertoire of natural variations existing at distinct molecular levels for an important human pathogen.