RFX6 is needed for the development and maintenance of the β-cell phenotype

RFX6 has recently been found to be essential for the development of the endocrine pancreas through studies in both humans and mice. Interestingly, this gene maintains a specific expression in the postnatal hormone producing cells of the pancreas. Moreover in humans, different types of diabetes mellitus affect obligate carriers of RFX6 mutations. Therefore, RFX6 appears to have a pivotal role in the maintenance of the phenotype of the β-cells in addition to their development. Extensive research is needed to specify this role and explore its significance in the efforts to treat diabetes with medications, or more importantly, through β-cell replacement.     

RFX6 is needed for the development and maintenance of the β-cell phenotype

RFX6 has recently been found to be essential for the development of the endocrine pancreas through studies in both humans and mice. Interestingly, this gene maintains a specific expression in the postnatal hormone producing cells of the pancreas. Moreover in humans, different types of diabetes mellitus affect obligate carriers of RFX6 mutations. Therefore, RFX6 appears to have a pivotal role in the maintenance of the phenotype of the β-cells in addition to their development. Extensive research is needed to specify this role and explore its significance in the efforts to treat diabetes with medications, or more importantly, through β-cell replacement.     

Notch-Hes1 pathway is required for the development of IL-17-producing γδ T cells

Unlike conventional T cells, which are exported from the thymus as naive cells and acquire effector functions upon antigen encounter in the periphery, a subset of γδ T cells differentiates into effectors that produce IL-17 within the fetal thymus. We demonstrate here that intrathymic development of the naturally occurring IL-17-producing γδ T cells is independent of STAT3 and partly dependent on RORγt. Comparative gene-expression analysis identified Hes1, one of the basic helix-loop-helix proteins involved in Notch signaling, as a factor specifically expressed in IL-17-producing γδ T cells. Hes1 is critically involved in the development of IL-17-producing γδ T cells, as evidenced by their severe decrease in the thymi of Hes1-deficient fetal mice. Delta-like 4 (Dll4)-expressing stromal cells support the development of IL-17-producing γδ T cells in vitro. In addition, conditional Hes1 ablation in peripheral γδ T cells decreases their IL-17 production but not their IFN-γ production. These results reveal a unique differentiation pathway of IL-17-producing γδ T cells.     

From the Cover: N-cadherin-dependent neuron–neuron interaction is required for the maintenance of activity-induced dendrite growth

Formation of neural circuits depends on stable contacts between neuronal processes, mediated by interaction of cell adhesion molecules, including N-cadherin. In the present study, we found that activity-dependent dendrite arborization specifically requires N-cadherin–mediated extracellular neuron–neuron interaction, because the enhancement did not occur for neurons cultured in isolation or plated on an astrocyte monolayer and was abolished by a recombinant soluble N-cadherin ectodomain. Furthermore, depolarization elevated the level of membrane-associated cadherin/catenin complexes and surface N-cadherin. Importantly, surface N-cadherin elevation is specifically required for the maintenance of nascent dendrite arbors. Through loss- and gain-of-function approaches, we showed that N-cadherin-mediated dendrite growth requires association of the cadherin/catenin complex with the actin cytoskeleton. In summary, these results identify a previously unexplored and specific function for activity-induced, N-cadherin–mediated neuron–neuron contacts in the maintenance of dendrite arbors.     

Nuclear factor-�� B inducing kinase is required for graft-versus-host disease

Background

Donor T lymphocytes are directly responsible for graft-versus-host disease. Molecules important in T-cell function may, therefore, be appropriate targets for graft-versus-host disease therapy and/or prophylaxis. Here we analyzed whether nuclear factor-κ B inducing kinase might have a role in graft-versus-host disease.

Design and Methods

We studied the expression of nuclear factor-κ B inducing kinase in human samples from patients with graft-versus-host disease. We also explored the effect of nuclear factor-κ B inducing kinase in a murine model of graft-versus-host disease using donor cells from aly/aly mice (deficient in nuclear factor-κ B inducing kinase) and C57BL/6 mice (control).

Results

We detected expression of nuclear factor-κ B inducing kinase in T-lymphocytes in the pathological lesions of patients with acute graft-versus-host disease. Mice transplanted with aly/aly T lymphocytes did not develop graft-versus-host disease at all, while mice receiving C57BL/6 cells died of a lethal form of the disease. Deficiency of nuclear factor-κ B inducing kinase did not affect the engrafting ability of donor T cells, but severely impaired their expansion capacity early after transplantation, and aly/aly T cells showed a higher proportion of apoptosis than did C57BL/6 T cells. Effector T lymphocytes were the T-cell subset most affected by nuclear factor-κ B inducing kinase deficiency. We also detected lower amounts of inflammatory cytokines in the serum of mice receiving aly/aly T cells than in the serum of mice receiving C57BL/6 T cells.

Conclusions

Our results show that nuclear factor-κ B inducing kinase has a role in graft-versus-host disease by maintaining the viability of activated alloreactive T lymphocytes.     

iRhom2 is required for the secretion of mouse TNFα

TNFα is a powerful inflammatory stimulus, central both to the control of infection, and as an agent of inflammatory disease. The most potent inducers of TNFα secretion signal through the Toll-like receptors, and we describe here a chemically-induced mutation that impairs this response in macrophages. A missense mutation was revealed in the gene encoding the inactive rhomboid protease iRhom2, which was not complemented by a null allele of the same gene. Neither the missense nor the null allele affected TLR-induced secretion of IL-6. Moreover, unlike a mutation in TNFα, the iRhom2 missense mutation did not cause enhanced susceptibility to colitis induced by dextran sodium sulfate. These results establish a specific role for iRhom2 in the secretion of TNFα, and present a new target for the modulation of inflammation.     

α-Actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca2+-activated K+ channel (SK2 channel)

The importance of proper ion channel trafficking is underpinned by a number of channel-linked genetic diseases whose defect is associated with failure to reach the cell surface. Conceptually, it is reasonable to suggest that the function of ion channels depends critically on the precise subcellular localization and the number of channel proteins on the cell surface membrane, which is determined jointly by the secretory and endocytic pathways. Yet the precise mechanisms of the entire ion channel trafficking pathway remain unknown. Here, we directly demonstrate that proper membrane localization of a small-conductance Ca²⁺-activated K⁺ channel (SK2 or K_Ca2.2) is dependent on its interacting protein, α-actinin2, a major F-actin crosslinking protein. SK2 channel localization on the cell-surface membrane is dynamically regulated, and one of the critical steps includes the process of cytoskeletal anchoring of SK2 channel by its interacting protein, α-actinin2, as well as endocytic recycling via early endosome back to the cell membrane. Consequently, alteration of these components of SK2 channel recycling results in profound changes in channel surface expression. The importance of our findings may transcend the area of K⁺ channels, given that similar cytoskeletal interaction and anchoring may be critical for the membrane localization of other ion channels in neurons and other excitable cells.     

Is neutropenia required for effective maintenance of remission during azathioprine therapy in inflammatory bowel disease?

BACKGROUND: Azathioprine is an effective treatment for maintaining remission in inflammatory bowel disease (IBD). It is a matter of debate as to whether neutropenia is required during azathioprine therapy to achieve more effective disease remission. We evaluated whether neutropenia during azathioprine therapy reduced relapse rates in IBD patients. PATIENTS AND METHODS: This retrospective study was based on a total of 173 IBD (96 Crohn's disease (CD), 77 ulcerative colitis (UC)) patients who were stable on azathioprine for a minimum of 6 months. Median duration of follow-up was 4.0 years (range 0.6-21 years). The lowest neutrophil counts during treatment for these patients were recorded. Relapse rates per year of follow-up were compared in non-neutropenic patients (neutrophil count > 2.5 x 10(9), n = 129) and neutropenic patients (neutrophil count < or = 2.5 x 10(9), n = 44) groups, and survival curves for cumulative remission rates compared by log-rank test. RESULTS: Mean relapse rate per year of follow-up for the non-neutropenic group was 0.19/year (SD = 0.37/year) compared with the neutropenic group 0.28/year (SD = 0.43/year) (P = NS). Analysis was performed on UC and CD subgroups, and relapse rates were not significantly different. The cumulative remission per cent determined by Kaplan-Meier survival analysis showed no difference between non-neutropenic and neutropenic groups by log-rank analysis, for UC and CD as well as for all IBD patients. CONCLUSION: Neutropenia < or = 2.5 x 10(9) while on azathioprine does not reduce the relapse rates of IBD patients who were established on azathioprine therapy compared with neutrophil counts > 2.5 x 10(9).