Pleiotropic functions of TNF-α in the regulation of the intestinal epithelial response to inflammation.

An important function of intestinal epithelial cells (IECs) is to maintain the integrity of the mucosal barrier. Inflammation challenges the integrity of the mucosal barrier and the intestinal epithelium needs to adapt to a multitude of signals in order to perform the complex process of maintenance and restitution of its barrier function. Dysfunctions in epithelial barrier integrity and restoration contribute to the pathogenesis of inflammatory bowel diseases (IBDs) such as Crohn's disease and ulcerative colitis.

Behavioral decline and premature lethality upon pan-neuronal ferritin overexpression in Drosophila infected with a virulent form of Wolbachia.

Iron is required for organismal growth. Therefore, limiting iron availability may be a key part of the host's innate immune response to various pathogens, for example, in Drosophila infected with Zygomycetes. One way the host can transiently reduce iron bioavailability is by ferritin overexpression.

Tpl2 regulates intestinal myofibroblast HGF release to suppress colitis-associated tumorigenesis.

The tumor microenvironment plays a significant role in colitis-associated cancer (CAC). Intestinal myofibroblasts (IMFs) are cells in the intestinal lamina propria secreting factors that are known to modulate carcinogenesis; however, the physiological role of IMFs and signaling pathways influencing CAC have remained unknown. Tumor progression locus 2 (Tpl2) is a MAPK that regulates inflammatory and oncogenic pathways.

Application of a novel strategy of engineering conditional alleles to a single exon gene, Sox2.

Background: The Conditional by Inversion (COIN) method for engineering conditional alleles relies on an invertible optimized gene trap-like element, the COIN module, for imparting conditionality. The COIN module contains an optimized 3' splice site-polyadenylation signal pair, but is inserted antisense to the target gene and therefore does not alter transcription, until it is inverted by Cre recombinase. In order to make COIN applicable to all protein-coding genes, the COIN module has been engineered within an artificial intron, enabling insertion into an exon.

Learning and memory deficits consequent to reduction of the fragile X mental retardation protein result from metabotropic glutamate receptor-mediated inhibition of cAMP signaling in Drosophila.

Loss of the RNA-binding fragile X protein [fragile X mental retardation protein (FMRP)] results in a spectrum of cognitive deficits, the fragile X syndrome (FXS), while aging individuals with decreased protein levels present with a subset of these symptoms and tremor. The broad range of behavioral deficits likely reflects the ubiquitous distribution and multiple functions of the protein. FMRP loss is expected to affect multiple neuronal proteins and intracellular signaling pathways, whose identity and interactions are essential in understanding and ameliorating FXS symptoms.

Twice is better: highlights of the second meeting focused on tau biology and pathology.

It is an exciting time for tau researchers as it is now generally accepted that abnormal tau species are required to mediate the toxic effects of amyloid β-peptide oligomers in Alzheimer's disease. Tau may play multiple roles in neurophysiology and there may be further pathologically relevant tau alterations, besides hyperphosphorylation and aggregation. The recent Biology and Pathology of Tau and its Role in Tauopathies II meeting explored these various aspects of tau, and presentations at the meeting, described in the following articles in this issue of Biochemical Society Transactions, are outlined in the present paper.

14-3-3ε Is required for germ cell migration in Drosophila.

Although 14-3-3 proteins participate in multiple biological processes, isoform-specific specialized functions, as well as functional redundancy are emerging with tissue and developmental stage-specificity. Accordingly, the two 14-3-3ε proteins in Drosophila exhibit functional specificity and redundancy. Homozygotes for loss of function alleles of D14-3-3ε contain significantly fewer germ line cells (pole cells) in their gonads, a phenotype not shared by mutants in the other 14-3-3 gene leo.

Identification of microRNA-221/222 and microRNA-323-3p association with rheumatoid arthritis via predictions using the human tumour necrosis factor transgenic mouse model.

Objective: To identify novel microRNA (miR) associations in synovial fibroblasts (SF), by performing miR expression profiling on cells isolated from the human tumour necrosis factor (TNF) transgenic mouse model (TghuTNF, Tg197) and patients biopsies.

Methods: miR expression in SF from TghuTNF and wild-type (WT) control mice were determined by miR deep sequencing (miR-seq) and the arthritic profile was established by pairwise comparisons. Quantitative PCR analysis was utilised for profile validation, miR and gene quantitation in patient SF.

Compartmentalization of bone morphogenetic proteins and their antagonists in lymphoid progenitors and supporting microenvironments and functional implications.

Bone morphogenetic protein (BMP) signalling regulates lymphopoiesis in bone marrow and thymus via the interaction of haemato-lymphoid progenitors with the stroma microenvironment. Despite increasing functional evidence for the role of BMP signalling in lymphopoiesis, little is known of the spatial distribution of BMP/BMP antagonists in the thymus and of how BMP signals exert specific functions in developing lymphocytes. We analysed expression of BMP/BMP antagonists in the thymus and bone marrow and determined the topology of BMP/BMP antagonist expression using lacZ reporter mice.

The receptor tyrosine kinase Alk controls neurofibromin functions in Drosophila growth and learning.

Anaplastic Lymphoma Kinase (Alk) is a Receptor Tyrosine Kinase (RTK) activated in several cancers, but with largely unknown physiological functions. We report two unexpected roles for the Drosophila ortholog dAlk, in body size determination and associative learning. Remarkably, reducing neuronal dAlk activity increased body size and enhanced associative learning, suggesting that its activation is inhibitory in both processes.

The power and richness of modelling tauopathies in Drosophila.

Tauopathies are a group of neurodegenerative disorders characterised by altered levels of phosphorylation or mutations in the neuronal microtubule protein Tau. The heterogeneous pathology of tauopathies suggests differential susceptibility of different neuronal types to wild-type and mutant Tau. The genetic power and facility of the Drosophila model has been instrumental in exploring the molecular aetiologies of tauopathies, identifying additional proteins likely contributing to neuronal dysfunction and toxicity and novel Tau phosphorylations mediating them.

Molecular vibration-sensing component in Drosophila melanogaster olfaction.

A common explanation of molecular recognition by the olfactory system posits that receptors recognize the structure or shape of the odorant molecule. We performed a rigorous test of shape recognition by replacing hydrogen with deuterium in odorants and asking whether Drosophila melanogaster can distinguish these identically shaped isotopes. We report that flies not only differentiate between isotopic odorants, but can be conditioned to selectively avoid the common or the deuterated isotope.

Phosphorylation differentiates tau-dependent neuronal toxicity and dysfunction.

The heterogeneous pathology of tauopathies and the differential susceptibility of different neuronal types to WT (wild-type) and mutant tau suggest that phosphorylation at particular sites rather than hyperphosphorylation mediates toxicity or dysfunction in a cell-type-specific manner. Pan-neuronal accumulation of tau in the Drosophila CNS (central nervous system) specifically affected the MBs (mushroom body neurons), consistent with neuronal type-specific effects. The MB aberrations depended, at least in part, on occupation of two novel phosphorylation sites: Ser(238) and Thr(245).

Two days of tau: a meeting focused on its biology and pathology.

Tauopathies are a clinically diverse group of neurodegenerative dementias involving perturbations of the level or phosphorylation state of the microtubule-binding axonal protein tau. Despite intense effort in recent years, the precise role of tau in the pathology of the various behaviourally and neuropathologically distinct tauopathies, the mechanisms of tau toxicity and the potential functional interaction of tau and amyloid in Alzheimer's disease remain elusive. Nevertheless, novel observations regarding the various aspects of taumisregulation-dependent pathogenesis are emerging from various cellular, vertebrate and invertebrate animal models and are supported by new clinical data.

Differential effects of Tau on the integrity and function of neurons essential for learning in Drosophila.

Tauopathies are a heterogeneous group of neurodegenerative dementias involving perturbations in the levels, phosphorylation, or mutations of the microtubule-binding protein Tau. The heterogeneous pathology in humans and model organisms suggests differential susceptibility of neuronal types to wild-type (WT) and mutant Tau. WT and mutant human Tau-encoding transgenes expressed pan-neuronally in the Drosophila CNS yielded specific and differential toxicity in the embryonic neuroblasts that generate the mushroom body (MB) neurons, suggesting cell type-specific effects of Tau in the CNS.

Dimerization is essential for 14-3-3zeta stability and function in vivo.

Members of the conserved 14-3-3 protein family spontaneously self-assemble as homo- and heterodimers via conserved sequences in the first four (alphaA-alphaD) of the nine helices that comprise them. Dimeric 14-3-3s bind conserved motifs in diverse protein targets involved in multiple essential cellular processes including signaling, intracellular trafficking, cell cycle regulation, and modulation of enzymatic activities. However, recent mostly in vitro evidence has emerged, suggesting functional and regulatory roles for monomeric 14-3-3s.

A third functional isoform enriched in mushroom body neurons is encoded by the Drosophila 14-3-3zeta gene.

14-3-3 proteins are highly conserved across eukaryotes, typically encoded by multiple genes in most species. Drosophila has only two such genes, 14-3-3zeta (leo), encoding two isoforms LEOI and LEOII, and 14-3-3epsilon. We report a bona fide third functional isoform encoded by leo divergent from the other two in structurally and functionally significant areas, thus increasing 14-3-3 diversity in Drosophila.

Control of thymic T cell maturation, deletion and egress by the RNA-binding protein HuR.

HuR emerged as a posttranscriptional regulator of mRNAs involved in cellular control, stress, and immunity but its role in governing such responses remains elusive. In this study, we assessed HuR's role in the staged progression of thymic T cell differentiation by means of its genetic ablation. Mice with an early deletion of HuR in thymocytes possess enlarged thymi but display a substantial loss of peripheral T cells.

A dual role for the adaptor protein DRK in Drosophila olfactory learning and memory.

Participation of RAS, RAF, and mitogen-activated protein kinase (MAPK) in learning and memory has been demonstrated in a number of studies, but the molecular events requisite for cascade activation and regulation have not been explored. We demonstrate that the adapter protein DRK (downstream of receptor kinase) which is essential for signaling to RAS in developmental contexts, is preferentially distributed in the adult mushroom bodies, centers for olfactory learning and memory. We demonstrate that drk mutant heterozygotes exhibit deficits in olfactory learning and memory, apparent under limited training conditions, but are not impaired in sensory responses requisite for the association of the stimuli, or brain neuroanatomy.

Modulation of growth factor action by the extracellular matrix.

Growth factors were historically defined as molecules produced by the body to regulate cell growth and proliferation. After the identification of their receptors and the intracellular signaling machinery they activate, it is now clear that they are involved in the regulation of multiple processes essential for development and normal tissue function. The present review gives a brief overview of growth factor action.

In vivo functional specificity and homeostasis of Drosophila 14-3-3 proteins.

The functional specialization or redundancy of the ubiquitous 14-3-3 proteins constitutes a fundamental question in their biology and stems from their highly conserved structure and multiplicity of coexpressed isotypes. We address this question in vivo using mutations in the two Drosophila 14-3-3 genes, leonardo (14-3-3zeta) and D14-3-3epsilon. We demonstrate that D14-3-3epsilon is essential for embryonic hatching.

Distinct neuronal circuits mediate experience-dependent, non-associative osmotactic responses in Drosophila.

Osmotactic responses can be modified in an experience-dependent manner and have been used to condition animals in negative or positive associative paradigms. Experience-dependent non-associative defects in avoidance of aversive odors were reported in Drosophila learning mutants. This prompted an examination of the contribution of the mushroom bodies and inner antenoglomerular tract, the two neuronal populations implicated in processing olfactory information to experience-dependent non-associative osmotactic responses.