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Target Recognition (target + recognition)
Selected AbstractsMyopodia (postsynaptic filopodia) participate in synaptic target recognitionDEVELOPMENTAL NEUROBIOLOGY, Issue 1 2003Sarah Ritzenthaler Abstract Synaptic partner cells recognize one another by utilizing a variety of molecular cues. Prior to neuromuscular synapse formation, Drosophila embryonic muscles extend dynamic actin-based filopodia called "myopodia." In wild-type animals, myopodia are initially extended randomly from the muscle surface but become gradually restricted to the site of motoneuron innervation, a spatial redistribution we call "clustering." Previous experiments with prospero mutant embryos demonstrated that myopodia clustering does not occur in the absence of motoneuron outgrowth into the muscle field. However, whether myopodia clustering is due to a general signal from passing axons or is a result of the specific interactions between synaptic partners remained to be investigated. Here, we have examined the relationship of myopodia to the specific events of synaptic target recognition, the stable adhesion of synaptic partners. We manipulated the embryonic expression of ,PS2 integrin and Toll, molecules known to affect synaptic development, to specifically alter synaptic targeting on identified muscles. Then, we used a vital single-cell labeling approach to visualize the behavior of myopodia in these animals. We demonstrate a strong positive correlation between myopodia activity and synaptic target recognition. The frequency of myopodia clustering is lowered in cases where synaptic targeting is disrupted. Myopodia clustering seems to result from the adherence of a subset of myopodia to the innervating growth cone while the rest are eliminated. The data suggest that postsynaptic cells play a dynamic role in the process of synaptic target recognition. © 2003 Wiley Periodicals, Inc. J Neurobiol 55: 31,40, 2003 [source] Forked end: a novel transmembrane protein involved in neuromuscular specificity in drosophila identified by gain-of-function screeningDEVELOPMENTAL NEUROBIOLOGY, Issue 3 2002Takeshi Umemiya Abstract The Drosophila neuromuscular connectivity provides an excellent model system for studies on target recognition and selective synapse formation. To identify molecules involved in neuromuscular recognition, we conducted gain-of-function screening for genes whose forced expression in all muscles alters the target specificity. We report here the identification of a novel transmembrane protein, Forked end (FEND), encoded by the fend gene, by the said screening. When the FEND expression was induced in all muscles, motoneurons that normally innervate muscle 12 formed ectopic synapses on a neighboring muscle 13. The target specificity of these motoneurons was also altered in the loss-of-function mutant of fend. During embryonic development, fend mRNA was detected in a subset of cells in the central nervous system and in the periphery. These results suggest that FEND is a novel axon guidance molecule involved in neuromuscular specificity. © 2002 Wiley Periodicals, Inc. J Neurobiol 51: 205,214, 2002 [source] New approaches in the immunotherapy of haematological malignanciesEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2003Régis T. Costello Abstract: Advances in the management of haematological malignancies have allowed to obtain improved remission rates. Nonetheless, relapses impair these results and justify the search for novel therapeutic strategies. Clinical data demonstrate that the immune system plays an important role in the control of haematological malignancies. An increased frequency of haematological malignancies is observed in immunodeficiency states. Reversal of the immunosuppression is sometimes sufficient to induce tumour regression (withdrawal of cyclosporine in post-transplant lymphoproliferations, highly active anti-retroviral treatment in human immunodeficiency virus related Kaposi's disease). Another line of evidence for the involvement of the immune system in the anti-tumour response comes from the observation of spontaneous anti-tumour responses that parallel the occurrence of paraneoplastic immune-mediated syndromes. Finally, the efficiency of allogeneic transplantation in the haematological field has been clearly demonstrated to depend on the immune-mediated graft vs. leukaemia effect. Nonetheless, tumours develop in immune competent patients because of various tumour escape mechanisms, such as loss of human leucocyte antigen class I antigens, absence of target recognition by deficient adhesion/co-stimulatory molecule expression, tumour cell counterattack against immune effectors, direct (contact-dependent) or indirect (cytokine-mediated) impairment of T-lymphocyte activation. Novel immunotherapy approaches are now orientated in a convergent direction, i.e. the reversal of immune escape mechanisms either via the correction of deficient phases of the immune response or by the amplification of physiological mechanisms. [source] Requirement of cannabinoid CB1 receptors in cortical pyramidal neurons for appropriate development of corticothalamic and thalamocortical projectionsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2010Chia-Shan Wu Abstract A role for endocannabinoid signaling in neuronal morphogenesis as the brain develops has recently been suggested. Here we used the developing somatosensory circuit as a model system to examine the role of endocannabinoid signaling in neural circuit formation. We first show that a deficiency in cannabinoid receptor type 1 (CB1R), but not G-protein-coupled receptor 55 (GPR55), leads to aberrant fasciculation and pathfinding in both corticothalamic and thalamocortical axons despite normal target recognition. Next, we localized CB1R expression to developing corticothalamic projections and found little if any expression in thalamocortical axons, using a newly established reporter mouse expressing GFP in thalamocortical projections. A similar thalamocortical projection phenotype was observed following removal of CB1R from cortical principal neurons, clearly demonstrating that CB1R in corticothalamic axons was required to instruct their complimentary connections, thalamocortical axons. When reciprocal thalamic and cortical connections meet, CB1R-containing corticothalamic axons are intimately associated with elongating thalamocortical projections containing DGL,, a 2-arachidonoyl glycerol (2-AG) synthesizing enzyme. Thus, 2-AG produced in thalamocortical axons and acting at CB1Rs on corticothalamic axons is likely to modulate axonal patterning. The presence of monoglyceride lipase, a 2-AG degrading enzyme, in both thalamocortical and corticothalamic tracts probably serves to restrict 2-AG availability. In summary, our study provides strong evidence that endocannabinoids are a modulator for the proposed ,handshake' interactions between corticothalamic and thalamocortical axons, especially for fasciculation. These findings are important in understanding the long-term consequences of alterations in CB1R activity during development, a potential etiology for the mental health disorders linked to prenatal cannabis use. [source] Structural basis of target recognition by Atg8/LC3 during selective autophagyGENES TO CELLS, Issue 12 2008Nobuo N. Noda Autophagy is a non-selective bulk degradation process in which isolation membranes enclose a portion of cytoplasm to form double-membrane vesicles, called autophagosomes, and deliver their inner constituents to the lytic compartments. Recent studies have also shed light on another mode of autophagy that selectively degrades various targets. Yeast Atg8 and its mammalian homologue LC3 are ubiquitin-like modifiers that are localized on isolation membranes and play crucial roles in the formation of autophagosomes. These proteins are also involved in selective incorporation of specific cargo molecules into autophagosomes, in which Atg8 and LC3 interact with Atg19 and p62, receptor proteins for vacuolar enzymes and disease-related protein aggregates, respectively. Using X-ray crystallography and NMR, we herein report the structural basis for Atg8,Atg19 and LC3,p62 interactions. Remarkably, Atg8 and LC3 were shown to interact with Atg19 and p62, respectively, in a quite similar manner: they recognized the side-chains of Trp and Leu in a four-amino acid motif, WXXL, in Atg19 and p62 using hydrophobic pockets conserved among Atg8 homologues. Together with mutational analyses, our results show the fundamental mechanism that allows Atg8 homologues, in association with WXXL-containing proteins, to capture specific cargo molecules, thereby endowing isolation membranes and/or their assembly machineries with target selectivity. [source] Neuronal cell adhesion molecule deletion induces a cognitive and behavioral phenotype reflective of impulsivityGENES, BRAIN AND BEHAVIOR, Issue 4 2008L. D. Matzel Cell adhesion molecules, such as neuronal cell adhesion molecule (Nr-CAM), mediate cell,cell interactions in both the developing and mature nervous system. Neuronal cell adhesion molecule is believed to play a critical role in cell adhesion and migration, axonal growth, guidance, target recognition and synapse formation. Here, wild-type, heterozygous and Nr-CAM null mice were assessed on a battery of five learning tasks (Lashley maze, odor discrimination, passive avoidance, spatial water maze and fear conditioning) previously developed to characterize the general learning abilities of laboratory mice. Additionally, all animals were tested on 10 measures of sensory/motor function, emotionality and stress reactivity. We report that the Nr-CAM deletion had no impact on four of the learning tasks (fear conditioning, spatial water maze, Lashley maze and odor discrimination). However, Nr-CAM null mice exhibited impaired performance on a task that required animals to suppress movement (passive avoidance). Although Nr-CAM mutants expressed normal levels of general activity and body weights, they did exhibit an increased propensity to enter stressful areas of novel environments (the center of an open field and the lighted side of a dark/light box), exhibited higher sensitivity to pain (hot plate) and were more sensitive to the aversive effects of foot shock (shock-induced freezing). This behavioral phenotype suggests that Nr-CAM does not play a central role in the regulation of general cognitive abilities but may have a critical function in regulating impulsivity and possibly an animal's susceptibility to drug abuse and addiction. [source] Quantitative specificity-based display library screening identifies determinants of antibody-epitope binding specificity,PROTEIN SCIENCE, Issue 9 2009Sejal S. Hall Abstract Despite the critical importance of molecular specificity in bimolecular systems, in vitro display technologies have been applied extensively for affinity maturation of peptides and antibodies without explicitly measuring the specificity of the desired interaction. We devised a general strategy to measure, screen, and evolve specificity of protein ligand interactions analogous to widely used affinity maturation strategies. The specificity of binding to target and nontarget antibodies labeled with spectrally distinct fluorophores was measured simultaneously in protein mixtures via multiparameter flow cytometry, thereby enabling screening for high target antibody specificity. Isolated antibody specific ligands exhibited varying specificity, revealing critical amino acid determinants for target recognition and nontarget avoidance in complex mixtures. Molecular specificity in the mixture was further enhanced by quantitative directed evolution, yielding a family of epitopes exhibiting improved specificities equivalent, or superior to, the native peptide antigen to which the antibody was raised. Specificity screening simultaneously favored affinity, yielding ligands with three-fold improved affinity relative to the parent epitope. Quantitative specificity screening will be useful to screen, evolve, and characterize the specificity of protein and peptide interactions for molecular recognition applications. [source] Activity-Based Protein Profiling for Type I Methionine Aminopeptidase by Using Photo-Affinity Trimodular ProbesCHEMBIOCHEM, Issue 12 2007Wen-Wei Qiu Dr. Three in one. A trimodular probe (1) with three functional groups (for target recognition, proximal target crosslinking, and distal reporter tag attachment via click chemistry of a photostable azido-acetyl group) has been designed. We demonstrate its specificity, sensitivity, and potential for general application in activity-based protein profiling for type I methionine aminopeptidases. [source] | |||||||||||||