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In brief: June 2008DNA repair HP1- Phosphorylation of the histone variant H2AX is the earliest known marker of DNA breakage. Ayoub et al. now report an upstream signalling cascade: DNA breaks mobilize heterochromatin protein-1 (HP1)- Nuclear envelope Otefin, a nuclear membrane protein, determines the fate of germline stem cells in Drosophila via interaction with Smad complexes The highly conserved nuclear lamin Ig-fold binds to PCNA: its role in DNA replication The physiological roles of nuclear lamins have been elusive. Jiang et al. now show that the Drosophila melanogaster nuclear lamin Otefin (OTE) is essential for germline stem cell (GSC) maintenance. OTE silences bam transcription in a Decapentaplegic (a TGF Mucosal immunology ROR Intraepithelial lymphocytes (IELs) of the gut and other body surfaces comprise the largest peripheral T-cell pool in the body. Whereas about half of IELs originate from the thymus, the origin of the rest has been a subject of debate. Gut cryptopatches — small organized structures containing immature LIN-CD25+IL-7R+KIT+ haematopoietic cells — could be a potential source of local IEL precursors. But other groups suggest instead that cryptopatch cells are the adult counterparts of ROR Immune regulation TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis A newly discovered member of the tumour-necrosis-factor- B-cell signalling Foxo1 directly regulates the transcription of recombination-activating genes during B cell development The authors sought to determine what factors were involved in the regulation of recombination-activating gene 1 (RAG1) and RAG2 during B-cell development. Using a retroviral cDNA library screen, they found that the stress-regulated protein GADD45a induced Rag1 transcription through the activation of the kinase p38 and the transcription factor FOXO1, and that FOXO1 could bind directly to the Rag locus. Further analysis showed that FOXO1 also regulated Rag1 transcription in developing primary B cells and 'knockdown' of FOXO1 expression resulted in reduced Rag1 and Rag2 transcription in a model of receptor editing. In addition, they found that the suppression of Rag1 transcription in both pro-B cells and immature B cells, induced by interleukin-7 receptor and B-cell receptor signalling, respectively, was through, in part, the PI3K- and AKT-signalling pathway. Inhibition of AKT increased Rag1 transcription and decreased FOXO1 phosphorylation. Metabolism The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator Conflicting data have led to the question of whether sirtuin 1 (SIRT1), thought to be a key mediator of the tumour-suppressive effects of calorie restriction, is an oncogene or a tumour suppressor in vivo. Using the Apcmin/+ mouse model of colon cancer, Firestein and colleagues found that SIRT1 deacetylates Angiogenesis Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth It has been proposed that angiogenesis and consequently tumour growth could depend on circulating VEGFR2+ (vascular endothelial growth factor receptor 2) endothelial progenitor cells, which are mobilized from the bone marrow (BM) by VEGF or tumour-derived chemokines. Using four different mouse models, Purhonen and colleagues found that subcutaneous injection of VEGF or the presence of tumours (melanoma xenografts or adenomas in Apcmin/+ mice) did not induce the mobilization of VEGFR2+ endothelial progenitors and that BM-derived endothelial cells did not contribute to the vascular endothelium or promote tumour growth. This data brings into question the rationale behind the current attempts to target BM-derived endothelial progenitors for anticancer therapy. Evolution Null mutations in human and mouse orthologs frequently result in different phenotypes An assumption of comparative genomics studies is that orthologous genes have similar functions and phenotypes across organisms. In their systematic survey of null mutant phenotypes, the authors have found that over 20% of essential human genes have non-essential mouse orthologues, and that the change in function has been caused by adaptations in the protein-coding sequence rather than in gene expression. The study might have implications for comparative studies of more divergent species. Axon guidance Alternative splicing of the Robo3 axon guidance receptor governs the midline switch from attraction to repulsion Growing axons are alternately attracted towards and repelled from a series of intermediate targets, through the carefully coordinated expression of specific guidance receptors. Now researchers show that two isoforms of the SLIT receptor ROBO3 are expressed in specific locations on the growing axons of commissural neurons in the spinal cord. ROBO3.1 is expressed on axons as they approach the midline and attracts them towards the midline, whereas expression of ROBO3.2 on axons after they cross the midline directs them away from this region. Excitotoxicity Prion protein attenuates excitotoxicity by inhibiting NMDA receptors The functional roles of the endogenous prion protein PrPC are not well understood. In this study, the authors show that basal excitability and levels of NMDA receptor (NMDAR)-mediated excitotoxic cell death in hippocampal neurons are increased in PrP-null mice. They show that this results from an increase in the activity of NMDARs containing the NR2D subunit. This suggests that PrPC plays an important part in synaptic function and neuroprotection by inhibiting NR2D-containing receptors. Neurodegenerative disease Light-activated channels targeted to ON bipolar cells restore visual function in retinal degeneration The degeneration of retinal photoreceptor cells is the underlying cause of blindness in conditions such as retinitis pigmentosa. Here the authors expressed the light-sensitive ion channel channelrhodopsin 2 in 'ON' bipolar cells — those that are normally activated by increased light levels — in a mouse model of retinal degeneration. Exposure to high-intensity light generated responses in the ganglion cells to which the bipolar cells project and in the visual cortex. Furthermore, the mice responded to light in several behavioural tests, providing hope that this technology might be translated to the human retina. Synaptic plasticity Expression of long-term depression underlies visual recognition memory Long-term potentiation and long-term depression (LTP and LTD) are thought to underlie learning and memory, although direct evidence for a causal relationship is scarce. The authors showed that preventing the internalization of the AMPA receptor (AMPAR) in vitro, by inhibiting the interaction between the AMPAR GluR2 subunit and the clathrin adaptor protein AP2, blocked LTD in slices of perirhinal cortex. Crucially, preventing this interaction in vivo disrupted visual recognition memory in rats, and LTD could not be induced in perirhinal cortex slices from these animals, indicating that LTD is required for visual recognition memory. Pulmonary disorders Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis Microbial lung infections are a major cause of morbidity in patients with cystic fibrosis. Teichgräber and colleagues showed that deficiency of Cftr in mice resulted in the accumulation of cellular ceramide in the respiratory tract, caused by the alkalinization of Cftr-deficient vesicles in respiratory cells. Accumulation of ceramide was also detected in respiratory epithelial cells and airways of subjects with cystic fibrosis. Normalization of pulmonary ceramide — such as with amitriptyline — prevented chronic pulmonary inflammation, impairment of mucociliary clearance and high susceptibility to severe infections. Anticancer drugs SGX393 inhibits the CML mutant Bcr–AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib T315I mutations in the oncogenic tyrosine kinase Bcr–Abl leads to chronic myeloid leukaemia (CML) that is resistant to all ABL kinase inhibitors — imatinib, nilotinib and dasatinib — that are in clinical use. O'Hare and colleagues identified an inhibitor, SGX393, that blocked the growth of leukaemia cell lines, primary haematopoietic cells and in vivo xenografts that expressed Bcr–AblT315I. Combining SGX393 with nilotinib or dasatinib pre-empted the emergence of resistant subclones, including Bcr–AblT315I, suggesting that this strategy may be useful for reduction of Bcr–Abl mutants in CML. Cell biology Red-shifted channelrhodopsin The microbial light-activated proteins channelrhodopsin-2 (ChR2) and halorhodopsin are powerful tools for stimulating mammalian neurons. There has been great interest in generating a red-shifted variant of the blue light–driven ChR2 to develop new applications of the technology. Zhang et al. now describe such a tool, the VChR1 channelrhodopsin from Volvox carteri, which they discovered by genome database searching. ChR2 and the yellow light–stimulated VChR1 can be activated separately, which will facilitate studies of circuit behavior. Immunochemistry A monoclonal antibody to Ago2 Members of the Argonaute (Ago) protein family serve as binding partners of small RNAs and are important in regulating gene expression. Biochemical analyses of Ago complexes thus far, however, have required overexpression of tagged Ago proteins. Rüdel et al. now report the development of a highly specific monoclonal antibody to Ago2 and demonstrate its application in western blotting, immunoprecipitation and immunofluorescence. | |
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mobilization promotes chromatin changes that initiate the DNA damage response
t is dispensable for the development of intestinal mucosal T cells
-induced protein 8 (TNFAIP8) family known as TIPE2 has been identified as a crucial regulator of immune responses. This protein was found to negatively regulate T-cell activation, as well as Toll-like receptor signalling in innate immune cells and B cells. Accordingly, TIPE2-deficient mice spontaneously developed fatal autoimmunity and were more susceptible to endotoxin-induced septic shock than wild-type mice. Closer examination of the molecular function of TIPE2 revealed its ability to inhibit the pro-inflammatory activator protein 1 (AP1) and nuclear factor-
B (NF-