Gata1 regulates dendritic-cell development and survival

Gutiérrez, Laura; Nikolić, Tatjana; Dijk, Thamar B. van; Hammad, Hamida; Vos, Nanda; Willart, Monique; Grosveld, Frank; Philipsen, Sjaak; Lambrecht, Bart N.

doi:10.1182/blood-2006-09-048322

Cited by 56 publications

(75 citation statements)

References 57 publications

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“…Importantly, we have also specifically shown the ability of the prototypic hemopoietic transcription factor GATA1 to regulate D6 expression and this is in keeping with the known importance of GATA1 for differentiation along many of the lineages we show here to be positive for D6 expression (32,33,41). Both primary human DCs and mouse bone marrow-derived DC cultures express high levels of D6.…”

Section: Discussionsupporting

confidence: 54%

“…Notably, the promoters (as shown for the mouse and human promoters in Fig. 1C) were seen to contain binding sites for a variety of transcription factors associated with hemopoietic lineagespecific differentiation (32,33). These include Ikaros (suggestive of T cell and DC expression), Myb (megakaryocyte expression), and FIGURE 1.…”

Section: D6 Is Expressed By Leukocytes In Inflamed Tissuesmentioning

confidence: 99%

“…This aspect of our study took advantage of previously generated mice bearing a "floxed" GATA1 allele and a tamoxifen (Tx)-inducible cre-recombinase transgene (32) from which DC cultures were generated. DCs were either generated from untreated mice, and then treated in vitro with Tx to induce GATA1 deletion, or from previously Tx-treated mice.…”

Section: Figure 5 Expression Of D6 Is Regulated By Gata1mentioning

confidence: 99%

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Hemopoietic Cell Expression of the Chemokine Decoy Receptor D6 Is Dynamic and Regulated by GATA1

McKimmie

Fraser

Hansell

et al. 2008

The Journal of Immunology

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D6 scavenges inflammatory chemokines and is essential for the regulation of inflammatory and immune responses. Mechanisms explaining the cellular basis for D6 function have been based on D6 expression by lymphatic endothelial cells. In this study, we demonstrate that functional D6 is also expressed by murine and human hemopoietic cells and that this expression can be regulated by pro- and anti-inflammatory agents. D6 expression was highest in B cells and dendritic cells (DCs). In myeloid cells, LPS down-regulated expression, while TGF-β up-regulated expression. Activation of T cells with anti-CD3 and soluble CD28 up-regulated mRNA expression 20-fold, while maturation of human macrophage and megakaryocyte precursors also up-regulated D6 expression. Competition assays demonstrated that chemokine uptake was D6 dependent in human leukocytes, whereas mouse D6-null cells failed to uptake and clear inflammatory chemokines. Furthermore, we present evidence indicating that D6 expression is GATA1 dependent, thus explaining D6 expression in myeloid progenitor cells, mast cells, megakaryocytes, and DCs. We propose a model for D6 function in which leukocytes, within inflamed sites, activate D6 expression and thus trigger resolution of inflammatory responses. Our data on D6 expression by circulating DCs and B cells also suggest alternative roles for D6, perhaps in the coordination of innate and adaptive immune responses. These data therefore alter our models of in vivo D6 function and suggest possible discrete, and novel, roles for D6 on lymphatic endothelial cells and leukocytes.

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Section: Discussionsupporting

confidence: 54%

Section: D6 Is Expressed By Leukocytes In Inflamed Tissuesmentioning

confidence: 99%

Section: Figure 5 Expression Of D6 Is Regulated By Gata1mentioning

confidence: 99%

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Hemopoietic Cell Expression of the Chemokine Decoy Receptor D6 Is Dynamic and Regulated by GATA1

McKimmie

Fraser

Hansell

et al. 2008

The Journal of Immunology

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“…We have demonstrated that GATA1 is a physiological regulator of D6 expression [75] using mice with a conditional deletion in GATA1 [78]. In DC of these mice, the knockdown of GATA1 is associated with a transcriptional switch-off of D6 expression confirming a role for GATA1 in the regulation of D6 expression.…”

Section: Regulation Of D6 Expressionmentioning

confidence: 95%

D6 and the atypical chemokine receptor family: Novel regulators of immune and inflammatory processes

2009

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Chemokines are key regulators of leukocyte migration and play important roles in a number of physiological and pathological immune and inflammatory contexts. In addition to the classical signalling chemokine receptors there has emerged, recently, a new subclass of atypical chemokine receptors. This subfamily is characterised by an apparent lack of signalling and, in some cases, by an ability to internalise and degrade chemokine ligands. This review describes the family of atypical chemokine receptors with particular emphasis on the D6 receptor. The in vitro and in vivo biology of D6 is described, which indicates that D6 is active as a scavenger of inflammatory CC-chemokines and appears to play essential roles in the regulation of inflammatory responses.Key words: Chemokines . Immune regulation . Inflammation IntroductionThe movement of leukocytes during immune and inflammatory responses is a carefully orchestrated process that ensures coordinated cellular migration in response to physiological and pathological cues. Prominent amongst the regulators of leukocyte movement are the members of the chemokine family [1]. Chemokines are small proteins (8-12 kDa) and membership of the chemokine family is defined on the basis of the presence of variations on a conserved cysteine motif in the mature section of the proteins. Chemokines can be assigned to one of four subfamilies according to the specific nature of this motif. The majority of chemokines have four cysteines with 28 chemokines being assigned to the CC family (so-called because of the juxtaposition of the first two cysteine residues) and 16 being assigned to the CXC family (which possess a single variable amino acid between the first two cysteines). The two smaller subfamilies are represented by single members and are the CX3C family (three amino acids between the first two cyteines) and the XC family, which lacks the first and third cyteines seen in the other family members. Much confusion arose in the mid-1990s due to the complex and variable nomenclature used to refer to chemokines. For this reason a systematic nomenclature system has been adopted, which refers to the chemokines as ligands of each of the subfamilies and numbers them according to when their sequences were first deposited in the Genbank databases [2]. Thus, CCL1 is the first CC chemokine to be identified and CCL28 the most recent. Chemokines and their roles in leukocyte migrationFunctionally, chemokines are known to be pleiotropic. However, their main role is in the regulation of leukocyte migration. In this context we can define chemokines as being either homeostatic/ constitutive or inflammatory according to the contexts in which they function [2,3]. Homeostatic chemokinesThe homeostatic chemokines are important for the regulation of basal leukocyte trafficking and regulate processes such as the Mini-Reviewtissue-specific migration of T cells and the homing of DC to draining lymph nodes [4][5][6]. In combination with adhesion molecules, the homeostatic chemokines can form part of a very spec...

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“…The WBC counts were not significantly altered during the course of Tx treatment ( Figure 3C), although in a separate study we found that Gata1 loss affected differentiation and survival of eosinophils and dendritic cells. 2 To investigate whether the KO-Tx mice respond to the induced anemic condition, we measured Epo levels in plasma ( Figure 3D). In KO-Tx mice at week 3, these ranged from 200 to 1000 pg/mL, which was up to 5-fold higher than normal levels.…”

Section: Gata1 Deficiency In Adult Erythropoiesis 4379mentioning

confidence: 99%

Ablation of Gata1 in adult mice results in aplastic crisis, revealing its essential role in steady-state and stress erythropoiesis

Gutiérrez¹,

Tsukamoto

Suzuki

et al. 2008

Blood

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The transcription factor Gata1 is expressed in several hematopoietic lineages and plays essential roles in normal hematopoietic development during embryonic stages. The lethality of Gata1-null embryos has precluded determination of its role in adult erythropoiesis. Here we have examined the effects of Gata1 loss in adult erythropoiesis using conditional Gata1 knockout mice expressing either interferon-or tamoxifen-inducible Cre recombinase (Mx-Cre and Tx-Cre, respectively). Mx-Cre-mediated Gata1 recombination, although incomplete, resulted in maturation arrest of Gata1-null erythroid cells at the proerythroblast stage, thrombocytopenia, and excessive proliferation of megakaryocytes in the spleen. Tx-Cremediated Gata1 recombination resulted in depletion of the erythroid compartment in bone marrow and spleen. Formation of the early and late erythroid progenitors in bone marrow was significantly reduced in the absence of Gata1. Furthermore, on treatment with a hemolytic agent, these mice failed to activate a stress erythropoietic response, despite the rising erythropoietin levels. These results indicate that, in addition to the requirement of Gata1 in adult megakaryopoiesis, Gata1 is necessary for steady-state erythropoiesis and for erythroid expansion in response to anemia. Thus, ablation of Gata1 in adult mice results in a condition resembling aplastic crisis in human. IntroductionProduction of mature blood cells from the pluripotent hematopoietic stem cells is continuous throughout life. This process is controlled by combinatorial functions of lineage-specific and ubiquitous transcription factors. The zinc finger transcription factor Gata1 is a prototype of lineage-specific transcription factors, with restricted expression in several myeloid lineages. 1,2 Gene ablation studies of Gata1 in mice revealed its essential role in erythroid cell development. Embryos lacking Gata1 die at approximately embryonic day 11.5 because of arrested maturation of primitive erythroid cells. 3 A similar phenotype was observed in embryos bearing a Gata1 knockdown mutation (Gata1.05) that causes 95% reduction of Gata1 mRNA level in erythroid cells. 4 A critical role for Gata1 in megakaryocyte maturation and platelet formation has been shown in mice with megakaryocyte-specific Gata1 deficiency. 5,6 A remarkable phenotype of these mutant mice is that defective maturation of megakaryocytes is associated with excessive proliferation, suggesting that Gata1 inhibits cell proliferation during megakaryocytic maturation.Although roles for Gata1 in postnatal megakaryopoiesis have been thoroughly investigated, the embryonic lethality caused by Gata1 deficiency in erythroid precursors has precluded studies of its role in postnatal erythropoiesis. In adults, the rate of red cell production in the steady-state condition is much lower than that in the fetal and neonatal stages. However, in response to erythropoietic stress, the rate of erythropoiesis is rapidly increased. 7 The plasma levels of erythropoietin (Epo), the central regulator of erythr...

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Gata1 regulates dendritic-cell development and survival

Cited by 56 publications

References 57 publications

Hemopoietic Cell Expression of the Chemokine Decoy Receptor D6 Is Dynamic and Regulated by GATA1

Hemopoietic Cell Expression of the Chemokine Decoy Receptor D6 Is Dynamic and Regulated by GATA1

D6 and the atypical chemokine receptor family: Novel regulators of immune and inflammatory processes

Ablation of Gata1 in adult mice results in aplastic crisis, revealing its essential role in steady-state and stress erythropoiesis

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