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Mariusz Z Ratajczak - One of the best experts on this subject based on the ideXlab platform.
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A Novel View of the Role of Prostaglandin E2 (PGE2) in Facilitating Engraftment of HSPCs By Activating the NOX2–ROS–Nlrp3 Inflammasome Axis to Incorporate the CXCR4 Receptor into Membrane Lipid Rafts
Blood, 2020Co-Authors: Magda Kucia, Kamila Bujko, Arjun Thapa, Janina Ratajczak, Mariusz Z RatajczakAbstract:Background . It is known that prostaglandin E2 (PGE2) increases the homing and engraftment of hematopoietic stem/progenitor cells (HSPCs). However, aside from its role in upregulation of CXCR4 Receptor expression on the surface of these cells, the exact mechanism has not been proposed. We have demonstrated in the past that an important step enabling the migration of HSPCs is the incorporation of CXCR4 into membrane lipid rafts on the leading surface (leading edge, in two dimensions) of migrating cells, which facilitates its interaction with cell migration signaling pathways (Wysoczynski M et al. Incorporation of CXCR4 into membrane lipid rafts primes homing-related responses of hematopoietic stem/progenitor cells to an SDF-1 gradient. Blood. 2005;105(1):40-48). Recently, we reported that Nlrp3 inflammasome-deficient HSPCs show a defect in lipid raft formation that results in defective migration of these cells in response to an SDF-1 gradient and their defective homing and engraftment after transplantation (Adamiak, M et al. Nlrp3 Inflammasome Signaling Regulates the Homing and Engraftment of Hematopoietic Stem Cells (HSPCs) by Enhancing Incorporation of CXCR4 Receptor into Membrane Lipid Rafts. Stem Cell Rev and Rep (2020). https://doi.org/10.1007/s12015-020-10005-w). An important activator of Nlrp3 inflammasomes is reactive oxygen species (ROS). Importantly, the enzyme that generates ROS, known as NADPH oxidase 2 (NOX2), is also associated with cell membrane lipid rafts. Hypothesis. Given the known roles of PGE2, membrane lipid rafts, and the Nlrp3 inflammasome in migration, homing, and engraftment of HSPCs, we hypothesized that PGE2 signaling promotes Nlrp3 inflammasome activation in a Nox2-ROS-dependent manner that results in incorporation of CXCR4 into membrane lipid rafts, which better explains the role of PGE2 in these phenomena.Materials and Methods. To test this hypothesis, murine SKL and human CD34+ cells enriched for HSPCs were stimulated with PGE2 to evaluate activation of genes of the Nlrp3 inflammasome complex at the mRNA and protein levels. Next, HSPCs from Nox2-KO mice were tested for membrane lipid raft formation in functional chemotaxis assays in response to SDF-1 gradients under conditions promoting membrane lipid raft formation. Formation of membrane lipid rafts in Nox2-KO cells was also evaluated by confocal analysis in the presence or absence of PGE2. Finally, the effect of the PGE2-Nox2-Nlrp3 inflammasome axis on the formation of membrane lipid rafts was evaluated in the presence of the ROS scavenger N-acethyl-cysteine (NAC). Results. We provide for the first time evidence that PGE2 activates Nlrp3 inflammasomes in HSPCs in a Nox2-ROS-dependent manner. This Nlrp3 inflammasome activation increases at the leading surface of migrating HSPCs with incorporation of the CXCR4 Receptor into membrane lipid rafts. Formation of membrane lipid rafts was absent in Nox2-KO and Nlrp3-KO mouse HSPCs and in normal wild type cells after their exposure to NAC. Moreover, we also observed that Nox2-KO and Nlrp3-KO mice had a lower basal level of CXCR4 expression. Conclusions. Our results for the first time explain the role of PGE2 in promoting homing and migration of HSPCs, which occurs in response to PGE2 by activation of the Nox2-ROS-Nlrp3 inflammasome axis and thereby promotes incorporation of the CXCR4 Receptor into membrane lipid rafts. Moreover, basal expression of the CXCR4 Receptor was at a low level on the surface of HSPCs from Nlrp3-KO mice. Thus, our results provide evidence for the importance of the Nox2-ROS-Nlrp3 inflammasome axis in PGE2-mediated homing and engraftment of HSPCs and the role of PGE2-mediated lipid raft formation for optimal responsiveness of CXCR4 to SDF-1 in the BM microenvironment. Disclosures No relevant conflicts of interest to declare.
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Nlrp3 Inflammasome Signaling Regulates the Homing and Engraftment of Hematopoietic Stem Cells (HSPCs) by Enhancing Incorporation of CXCR4 Receptor into Membrane Lipid Rafts
Stem Cell Reviews and Reports, 2020Co-Authors: Mateusz Adamiak, Magda Kucia, Kamila Bujko, Arjun Thapa, Krzysztof Anusz, Michał Tracz, Katarzyna Brzezniakiewicz-janus, Ahmed Abdel-latif, Janina Ratajczak, Mariusz Z RatajczakAbstract:Fast and efficient homing and engraftment of hematopoietic stem progenitor cells (HSPCs) is crucial for positive clinical outcomes from transplantation. We found that this process depends on activation of the Nlrp3 inflammasome, both in the HSPCs to be transplanted and in the cells in the recipient bone marrow (BM) microenvironment. For the first time we provide evidence that functional deficiency in the Nlrp3 inflammasome in transplanted cells or in the host microenvironment leads to defective homing and engraftment. At the molecular level, functional deficiency of the Nlrp3 inflammasome in HSPCs leads to their defective migration in response to the major BM homing chemoattractant stromal-derived factor 1 (SDF-1) and to other supportive chemoattractants, including sphingosine-1-phosphate (S1P) and extracellular adenosine triphosphate (eATP). We report that activation of the Nlrp3 inflammasome increases autocrine release of eATP, which promotes incorporation of the CXCR4 Receptor into membrane lipid rafts at the leading surface of migrating cells. On the other hand, a lack of Nlrp3 inflammasome expression in BM conditioned for transplantation leads to a decrease in expression of SDF-1 and danger-associated molecular pattern molecules (DAMPs), which are responsible for activation of the complement cascade (ComC), which in turn facilitates the homing and engraftment of HSPCs.
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Binding of stromal derived factor‐1α(SDF‐1α) to CXCR4 chemokine Receptorin normal human megakaryoblasts butnot in platelets induces phosphorylationof mitogen‐activated protein kinase p42/44 (MAPK), ELK‐1 transcription factor and serine/threonine kina
European journal of haematology, 2000Co-Authors: Marcin Majka, Janina Ratajczak, M. Anna Kowalska, Mariusz Z RatajczakAbstract:The aim of this study was to identify pathways which are involved in signal transduction from the CXCR4 Receptor stimulated by stromal derived factor-1alpha (SDF-1alpha) in human malignant hematopoietic cells and normal megakaryoblasts. First, we found that activation of CXCR4 in human T cell lines (Jurkat and ATL-2) rapidly induced phosphorylation of mitogen-activated protein kinases (MAPK) (p44 ERK-1 and p42 ERK-2). Next, we became interested in CXCR4-mediated signaling in normal hematopoietic cells, and employed human megakaryoblasts, which highly express CXCR4 as a model. We found that stimulation of these cells with SDF-1alpha led to the phosphorylation of MAPK and serine/threonine kinase AKT as well. Activation of MAPK further led to the phosphorylation of the nuclear transcription factor ELK-1. Phosphorylation of ELK-1 in megakaryoblasts implies that phosphorylated MAPK translocate from cytoplasm into the nucleus where they may phosphorylate some nuclear proteins. Note that neither MAPK nor AKT was phosphorylated in normal human platelets after stimulation by SDF-1. We conclude that both MAPK and AKT are involved in signal transduction pathways from the CXCR4 Receptor in malignant and normal human hematopoietic cells. The biological consequences of MAPK, ELK-1 and AKT phosphorylation in megakaryoblasts after stimulation with SDF-1alpha require further studies.
Kai-chia Yeh - One of the best experts on this subject based on the ideXlab platform.
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Development of Stem-Cell-Mobilizing Agents Targeting CXCR4 Receptor for Peripheral Blood Stem Cell Transplantation and Beyond
Journal of medicinal chemistry, 2018Co-Authors: Jen-shin Song, Hsuan‐hao Kuan, Ming-chen Chou, Jiing-jyh Jan, Lun Kelvin Tsou, Chiung-tong Chen, Kai-chia YehAbstract:The function of the CXCR4/CXCL12 axis accounts for many disease indications, including tissue/nerve regeneration, cancer metastasis, and inflammation. Blocking CXCR4 signaling with its antagonists may lead to moving out CXCR4+ cell types from bone marrow to peripheral circulation. We have discovered a novel series of pyrimidine-based CXCR4 antagonists, a representative (i.e., 16) of which was tolerated at a higher dose and showed better HSC-mobilizing ability at the maximal response dose relative to the approved drug 1 (AMD3100), and thus considered a potential drug candidate for PBSCT indication. Docking compound 16 into the X-ray crystal structure of CXCR4 Receptor revealed that it adopted a spider-like conformation striding over both major and minor subpockets. This putative binding mode provides a new insight into CXCR4 Receptor–ligand interactions for further structural modifications.
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Discovery of novel stem cell mobilizers that target the CXCR4 Receptor.
ChemMedChem, 2011Co-Authors: Chun-ping Chang, Jen-shin Song, Ming-chen Chou, Jiing-jyh Jan, Kai-chia Yeh, Ying‐chieh Wong, Chieh-jui Hsieh, Chiung-tong ChenAbstract:[[abstract]]Going mobile: Based on screening hit 1, a novel class of polyamine compounds, as represented by compound 8, were identified as potent and selective CXCR4 antagonists. CXCR4-targeted molecules, as demonstrated by the marketed AMD3100 and 8, are able to mobilize stem cells from bone marrow effectively and are expected to have broad utility in cell therapy and regenerative medicine
Thue W Schwartz - One of the best experts on this subject based on the ideXlab platform.
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molecular mechanism of action of monocyclam versus bicyclam non peptide antagonists in the CXCR4 chemokine Receptor
Journal of Biological Chemistry, 2007Co-Authors: Mette M. Rosenkilde, Lars Ole Gerlach, Renato T Skerlj, Dominique Schols, Sigrid Hatse, Gary Bridger, Thue W SchwartzAbstract:AMD3465 is a novel, nonpeptide CXCR4 antagonist and a potent inhibitor of HIV cell entry in that one of the four-nitrogen cyclam rings of the symmetrical, prototype bicyclam antagonist AMD3100 has been replaced by a two-nitrogen N-pyridinylmethylene moiety. This substitution induced an 8-fold higher affinity as determined against (125)I-12G5 monoclonal CXCR4 antibody binding, and a 22-fold higher potency in inhibition of CXCL12-induced signaling through phosphatidylinositol accumulation. Mutational mapping of AMD3465 and a series of analogs of this in a library of 23 mutants covering the main ligand binding pocket of the CXCR4 Receptor demonstrated that the single cyclam ring of AMD3465 binds in the pocket around AspIV:20 (Asp(171)), in analogy with AMD3100, whereas the N-pyridinylmethylene moiety mimics the other cyclam ring through interactions with the two acidic anchor-point residues in transmembrane (TM)-VI (AspVI:23/Asp(262)) and TM-VII (GluVII:06/Glu(288)). Importantly, AMD3465 has picked up novel interaction sites, for example, His(281) located at the interface of extracellular loop 3 and TM-VII and HisIII:05 (His(113)) in the middle of the binding pocket. It is concluded that the simple N-pyridinylmethylene moiety of AMD3465 substitutes for one of the complex cyclam moieties of AMD3100 through an improved and in fact expanded interaction pattern mainly with residues located in the extracellular segments of TM-VI and -VII of the CXCR4 Receptor. It is suggested that the remaining cyclam ring of AMD3465, which ensures the efficacious blocking of the Receptor, in a similar manner can be replaced by chemical moieties allowing for, for example, oral bioavailability.
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Molecular Mechanism of AMD3100 Antagonism in the CXCR4 Receptor TRANSFER OF BINDING SITE TO THE CXCR3 Receptor
The Journal of biological chemistry, 2003Co-Authors: Mette M. Rosenkilde, Lars Ole Gerlach, Renato T Skerlj, Gary J Bridger, Janus S. Jakobsen, Thue W SchwartzAbstract:Abstract AMD3100 is a symmetric bicyclam, prototype non-peptide antagonist of the CXCR4 chemokine Receptor. Mutational substitutions at 16 positions located in TM-III, -IV, -V, -VI, and -VII lining the main ligand-binding pocket of the CXCR4 Receptor identified three acid residues: Asp171 (AspIV:20), Asp262 (AspVI:23), and Glu288 (GluVII:06) as the main interaction points for AMD3100. Molecular modeling suggests that one cyclam ring of AMD3100 interacts with Asp171 in TM-IV, whereas the other ring is sandwiched between the carboxylic acid groups of Asp262 and Glu288 from TM-VI and -VII, respectively. Metal ion binding in the cyclam rings of AMD3100 increased its dependence on Asp262 and provided a tighter molecular map of the binding site, where borderline mutational hits became clear hits for the Zn(II)-loaded analog. The proposed binding site for AMD3100 was confirmed by a gradual build-up in the rather distinct CXCR3 Receptor, for which the compound normally had no effect. Introduction of only a Glu at position VII:06 and the removal of a neutralizing Lys residue at position VII:02 resulted in a 1000-fold increase in affinity of AMD3100 to within 10-fold of its affinity in CXCR4. We conclude that AMD3100 binds through interactions with essentially only three acidic anchor-point residues, two of which are located at one end and the third at the opposite end of the main ligand-binding pocket of the CXCR4 Receptor. We suggest that non-peptide antagonists with, for example, improved oral bioavailability can be designed to mimic this interaction and thereby efficiently and selectively block the CXCR4 Receptor.
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Metal ion enhanced binding of AMD3100 to Asp262 in the CXCR4 Receptor.
Biochemistry, 2003Co-Authors: Lars Ole Gerlach, Renato T Skerlj, Gary J Bridger, Janus S. Jakobsen, Kasper P. Jensen, Mette R. Rosenkilde, Ulf Ryde, Thue W SchwartzAbstract:The affinity of AMD3100, a symmetrical nonpeptide antagonist composed of two 1,4,8,11-tetraazacyclotetradecane (cyclam) rings connected through a 1,4-dimethylene(phenylene) linker to the CXCR4 chemokine Receptor was increased 7, 36, and 50-fold, respectively, by incorporation of the following: Cu2+, Zn2+, or Ni2+ into the cyclam rings of the compound. The rank order of the transition metal ions correlated with the calculated binding energy between free acetate and the metal ions coordinated in a cyclam ring. Construction of AMD3100 substituted with only a single Cu2+ or Ni2+ ion demonstrated that the increase in binding affinity of the metal ion substituted bicyclam is achieved through an enhanced interaction of just one of the ring systems. Mutational analysis of potential metal ion binding residues in the main ligand binding crevice of the CXCR4 Receptor showed that although binding of the bicyclam is dependent on both Asp171 and Asp262, the enhancing effect of the metal ion was selectively eliminated b...
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molecular interactions of cyclam and bicyclam non peptide antagonists with the CXCR4 chemokine Receptor
Journal of Biological Chemistry, 2001Co-Authors: Lars Ole Gerlach, Renato T Skerlj, Gary J Bridger, Thue W SchwartzAbstract:Abstract The non-peptide CXCR4 Receptor antagonist AMD3100, which is a potent blocker of human immunodeficiency virus cell entry, is a symmetrical bicyclam composed of two identical 1,4,8,11-tetraazacyclotetradecane (cyclam) moieties connected by a relatively rigid phenylenebismethylene linker. Based on the known strong propensity of the cyclam moiety to bind carboxylic acid groups, Receptor mutagenesis identified Asp171 and Asp262, located in transmembrane domain (TM) IV and TM-VI, respectively, at each end of the main ligand-binding crevice of the CXCR4 Receptor, as being essential for the ability of AMD3100 to block the binding of the chemokine ligand stromal cell-derived factor (SDF)-1α as well as the binding of the Receptor antibody 12G5. The free cyclam moiety had no effect on 12G5 binding, but blocked SDF-1α binding with an affinity of 3 μm through interaction with Asp171. The effect on SDF-1α binding of a series of bicyclam analogs with variable chemical linkers was found to rely either only on Asp171, i.e. the bicyclams acted as the isolated cyclam, or on both Asp171 and Asp262, i.e. they acted as AMD3100, depending on the length and the chemical nature of the linker between the two cyclam moieties. A positive correlation was found between the dependence of these compounds on Asp262 for binding and their potency as anti-human immunodeficiency virus agents. It is concluded that AMD3100 acts on the CXCR4 Receptor through binding to Asp171 in TM-IV and Asp262 in TM-VI with each of its cyclam moieties, and it is suggested that part of its function is associated with a conformational constraint imposed upon the Receptor by the connecting phenylenebismethylene linker.
Mario Mellado - One of the best experts on this subject based on the ideXlab platform.
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the chemokine sdf 1alpha triggers CXCR4 Receptor dimerization and activates the jak stat pathway
The FASEB Journal, 1999Co-Authors: Antonio J Vilacoro, Ana Martín De Ana, Jose Miguel Rodriguezfrade, Carmen M Morenoortiz, Carlos Martineza, Mario MelladoAbstract:The chemokine stromal cell-derived factor (SDF-1α), the ligand for the CXCR4 Receptor, induces a wide variety of effects that include calcium mobilization, chemotactic responses, bone marrow myelopoiesis, neuronal patterning, and prevention of HIV-1 infection. Nonetheless, little is known of the biochemical pathways required to achieve this variety of responses triggered after Receptor–chemokine interaction. We developed a set of monoclonal antibodies that specifically recognize the CXCR4 Receptor and used them to identify the signaling pathway activated after SDF-1α binding in human T cell lines. Here we demonstrate that SDF-1α activation promotes the physical association of Gαi with the CXCR4. Furthermore, within seconds of SDF-1α activation, the CXCR4 Receptor becomes tyrosine phosphorylated through the activation and association with the Receptor of JAK2 and JAK3 kinases. After SDF-1α binding, JAK2 and JAK3 associate with CXCR4 and are activated, probably by transphosphorylation, in a Gαi-independent ...
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The chemokine SDF-1alpha triggers CXCR4 Receptor dimerization and activates the JAK/STAT pathway.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 1999Co-Authors: Antonio J. Vila-coro, José Miguel Rodríguez-frade, Ana Martín De Ana, Ma Carmen Moreno‐ortíz, Carlos Martínez-a, Mario MelladoAbstract:The chemokine stromal cell-derived factor (SDF-1α), the ligand for the CXCR4 Receptor, induces a wide variety of effects that include calcium mobilization, chemotactic responses, bone marrow myelopoiesis, neuronal patterning, and prevention of HIV-1 infection. Nonetheless, little is known of the biochemical pathways required to achieve this variety of responses triggered after Receptor–chemokine interaction. We developed a set of monoclonal antibodies that specifically recognize the CXCR4 Receptor and used them to identify the signaling pathway activated after SDF-1α binding in human T cell lines. Here we demonstrate that SDF-1α activation promotes the physical association of Gαi with the CXCR4. Furthermore, within seconds of SDF-1α activation, the CXCR4 Receptor becomes tyrosine phosphorylated through the activation and association with the Receptor of JAK2 and JAK3 kinases. After SDF-1α binding, JAK2 and JAK3 associate with CXCR4 and are activated, probably by transphosphorylation, in a Gαi-independent ...
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The chemokine SDF‐1α triggers a chemotactic response and induces cell polarization in human B lymphocytes
European journal of immunology, 1998Co-Authors: Miguel Vicente-manzanares, Carlos Martínez-a, Mario Mellado, María C. Montoya, José María Frade, Miguel A. Del Pozo, Marta Nieto, Manuel O. Landázuri, Francisco Sánchez-madridAbstract:We studied the expression and possible functional role of chemokine Receptors CXCR3, CXCR4 and CCR5 in normal human B lymphocytes. B cells from both peripheral blood and tonsils expressed high levels of CXCR4 but not the other chemokine Receptors tested. CXCR4 ligand, stromal cell-derived factor (SDF)-1alpha, elicited a potent chemotactic response and induced a polarized motile phenotype in B cells, resulting in redistribution of the adhesion molecule ICAM-3 to a posterior appendage of the cell, termed uropod, and of CXCR4 Receptor to the leading edge of migrating B cells. Time-lapse videomicroscopy studies revealed that SDF-1alpha-treated cells recruited additional bystander B cells through the uropod. SDF-1alpha induced levels of cellular recruitment comparable to those elicited by polarization-inducing anti-ICAM-3 monoclonal antibody, in an LFA-1/ICAM-1, -3-dependent fashion. Moreover, this chemokine increased intracellular Ca2+ levels in B lymphocytes, and induced a rapid CXCR4 Receptor down-regulation on the cell surface membrane. These results provide new insight into the important biological role of SDF-1alpha in physiological processes in which B cells participate, and suggest a key role for chemokines in normal B cell trafficking and recirculation.
Richard J. Miller - One of the best experts on this subject based on the ideXlab platform.
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Discovery and characterization of novel small-molecule CXCR4 Receptor agonists and antagonists
Scientific reports, 2016Co-Authors: Rama K. Mishra, Richard J. Miller, Andrew K. Shum, Leonidas C. Platanias, Gary E. SchiltzAbstract:The chemokine CXCL12 (SDF-1) and its cognate Receptor CXCR4 are involved in a large number of physiological processes including HIV-1 infectivity, inflammation, tumorigenesis, stem cell migration and autoimmune diseases. While previous efforts have identified a number of CXCR4 antagonists, there have been no small molecule agonists reported. Herein, we describe the identification of a novel series of CXCR4 modulators, including the first small molecules to display agonist behavior against this Receptor, using a combination of structure- and ligand-based virtual screening. These agonists produce robust calcium mobilization in human melanoma cell lines which can be blocked by the CXCR4-selective antagonist AMD3100. We also demonstrate the ability of these new agonists to induce Receptor internalization, ERK activation and chemotaxis, all hallmarks of CXCR4 activation. Our results describe a new series of biologically relevant small molecules that will enable further study of the CXCR4 Receptor and may contribute to the development of new therapeutics.
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Regulation of CXCR4 Receptor Dimerization by the Chemokine SDF-1α and the HIV-1 Coat Protein gp120: A Fluorescence Resonance Energy Transfer (FRET) Study
The Journal of pharmacology and experimental therapeutics, 2004Co-Authors: Peter T. Toth, Dongjun Ren, Richard J. MillerAbstract:Both the chemokine SDF-1α and the human immunodeficiency virus-1 (HIV-1) coat protein gp120 can bind to CXCR4 chemokine Receptors but with different signaling consequences. To understand the molecular basis for these differences, we tagged the rat CXCR4 Receptor with enhanced cyan (ECFP) and yellow (EYFP) derivatives of the green fluorescent protein and investigated CXCR4 Receptor dimerization in human embryonic kidney (HEK)-tsA201 cells using fluorescence resonance energy transfer (FRET). Elevated FRET was detected under basal conditions from EYFP-CXCR4 and ECFP-CXCR4 Receptor-transfected cells indicating a high level of CXCR4 Receptor dimerization. In comparison, EYFP-CXCR4 and ECFP-μ-opioid Receptor-cotransfected cells displayed a much lower FRET signal. The FRET signal resulting from EYFP-CXCR4- and ECFP-CXCR4-expressing cells could be attenuated by coexpressing nontagged CXCR4 Receptors suggesting competition with fluorophore-tagged Receptors in the membrane. Nontagged μ-opioid, κ-opioid, and muscarinic Receptors also decreased the FRET between the tagged CXCR4 Receptor pairs but to a lesser extent. Application of the CXCR4 Receptor agonist SDF-1α (50 nM) further increased the FRET signal from tagged CXCR4 Receptors, an effect that was inhibited by the CXCR4 antagonist AMD3100. SDF-1α had no effect when EYFP-CXCR4 and ECFP-μ-opioid Receptors were coexpressed. The effect of gp120IIIB on CXCR4 FRET was dependent on the coexpression of human CD4 (hCD4) when it increased the FRET signal, and this was decreased by AMD3100 pretreatment. FRET analysis of tagged hCD4 constructs demonstrated that there was significant association of hCD4 and CXCR4, as well as hCD4 dimerization. These data suggest that CXCR4 dimerization is involved in SDF-1α- and gp120-induced signaling events.
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abnormal development of the hippocampal dentate gyrus in mice lacking the CXCR4 chemokine Receptor
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Elizabeth A Grove, Richard J. MillerAbstract:We investigated the role of the CXCR4 chemokine Receptor in development of the mouse hippocampus. CXCR4 mRNA is expressed at sites of neuronal and progenitor cell migration in the hippocampus at late embryonic and early postnatal ages. mRNA for stromal cell-derived factor 1 (SDF-1), the only known ligand for the CXCR4 Receptor, is expressed close to these migration sites, in the meninges investing the hippocampal primordium and the primordium itself. In mice engineered to lack the CXCR4 Receptor, the morphology of the hippocampal dentate gyrus (DG) is dramatically altered. Gene expression markers for DG granule neurons and bromodeoxyuridine labeling of dividing cells revealed an underlying defect in the stream of postmitotic cells and secondary dentate progenitor cells that migrate toward and form the DG. In the absence of CXCR4, the number of dividing cells in the migratory stream and in the DG itself is reduced, and neurons appear to differentiate prematurely before reaching their target. Our findings indicate a role for the SDF-1/CXCR4 chemokine signaling system in DG morphogenesis. Finally, the DG is unusual as a site of adult neurogenesis. We find that both CXCR4 and SDF-1 are expressed in the adult DG, suggesting an ongoing role in DG morphogenesis.
