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1

Hnatova, Martina, Micheline Wésolowski-Louvel, Guenaëlle Dieppois, Julien Deffaud, and Marc Lemaire. "Characterization of KlGRR1 and SMS1 Genes, Two New Elements of the Glucose Signaling Pathway of Kluyveromyces lactis." Eukaryotic Cell 7, no. 8 (2008): 1299–308. http://dx.doi.org/10.1128/ec.00454-07.

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ABSTRACT The expression of the major glucose transporter gene, RAG1, is induced by glucose in Kluyveromyces lactis. This regulation involves several pathways, including one that is similar to Snf3/Rgt2-ScRgt1 in Saccharomyces cerevisiae. We have identified missing key components of the K. lactis glucose signaling pathway by comparison to the same pathway of S. cerevisiae. We characterized a new mutation, rag19, which impairs RAG1 regulation. The Rag19 protein is 43% identical to the F-box protein ScGrr1 of S. cerevisiae and is able to complement an Scgrr1 mutation. In the K. lactis genome, we
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Prior, C., P. Mamessier, H. Fukuhara, X. J. Chen, and M. Wesolowski-Louvel. "The hexokinase gene is required for transcriptional regulation of the glucose transporter gene RAG1 in Kluyveromyces lactis." Molecular and Cellular Biology 13, no. 7 (1993): 3882–89. http://dx.doi.org/10.1128/mcb.13.7.3882-3889.1993.

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The RAG1 gene of Kluyveromyces lactis encodes a low-affinity glucose/fructose transporter. Its transcription is induced by glucose, fructose, and several other sugars. The RAG4, RAG5, and RAG8 genes are trans-acting genes controlling the expression of the RAG1 gene. We report here the characterization of one of these genes, RAG5. The nucleotide sequence of the cloned RAG5 gene indicated that it encodes a protein that is homologous to hexokinases of Saccharomyces cerevisiae. rag5 mutants showed no detectable hexokinase or glucokinase activity, suggesting that the sugar kinase activity encoded b
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3

Prior, C., P. Mamessier, H. Fukuhara, X. J. Chen, and M. Wesolowski-Louvel. "The hexokinase gene is required for transcriptional regulation of the glucose transporter gene RAG1 in Kluyveromyces lactis." Molecular and Cellular Biology 13, no. 7 (1993): 3882–89. http://dx.doi.org/10.1128/mcb.13.7.3882.

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The RAG1 gene of Kluyveromyces lactis encodes a low-affinity glucose/fructose transporter. Its transcription is induced by glucose, fructose, and several other sugars. The RAG4, RAG5, and RAG8 genes are trans-acting genes controlling the expression of the RAG1 gene. We report here the characterization of one of these genes, RAG5. The nucleotide sequence of the cloned RAG5 gene indicated that it encodes a protein that is homologous to hexokinases of Saccharomyces cerevisiae. rag5 mutants showed no detectable hexokinase or glucokinase activity, suggesting that the sugar kinase activity encoded b
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4

Naik, Abani Kanta, Aaron T. Byrd, Aaron C. K. Lucander, and Michael S. Krangel. "Hierarchical assembly and disassembly of a transcriptionally active RAG locus in CD4+CD8+ thymocytes." Journal of Experimental Medicine 216, no. 1 (2018): 231–43. http://dx.doi.org/10.1084/jem.20181402.

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Expression of Rag1 and Rag2 is tightly regulated in developing T cells to mediate TCR gene assembly. Here we have investigated the molecular mechanisms governing the assembly and disassembly of a transcriptionally active RAG locus chromatin hub in CD4+CD8+ thymocytes. Rag1 and Rag2 gene expression in CD4+CD8+ thymocytes depends on Rag1 and Rag2 promoter activation by a distant antisilencer element (ASE). We identify GATA3 and E2A as critical regulators of the ASE, and Runx1 and E2A as critical regulators of the Rag1 promoter. We reveal hierarchical assembly of a transcriptionally active chroma
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5

Fisher, Megan, and Craig Bassing. "Pre-B cells suppress RAG expression in response to DNA double-strand breaks (HEM1P.225)." Journal of Immunology 194, no. 1_Supplement (2015): 50.8. http://dx.doi.org/10.4049/jimmunol.194.supp.50.8.

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Abstract The ability of the Rag1/Rag2 (RAG) endonuclease to assemble antigen receptor (AgR) genes is essential for adaptive immunity. However, aberrant induction or repair of RAG-induced DNA double strand breaks (DSBs) can lead to oncogenic AgR translocations. We have previously shown that RAG-induced DSBs in pre-B cells activate the ATM kinase to prevent RAG cleavage of the homologous allele, and to inhibit expression of Rag1 and Rag2. These breaks also suppress expression of Gadd45α, which promotes Rag1 and Rag2 transcription. Since DSBs induced by ionizing radiation (IR) signal through ATM
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6

Hao, Bingtao, Abani Kanta Naik, Akiko Watanabe, et al. "An anti-silencer– and SATB1-dependent chromatin hub regulates Rag1 and Rag2 gene expression during thymocyte development." Journal of Experimental Medicine 212, no. 5 (2015): 809–24. http://dx.doi.org/10.1084/jem.20142207.

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Rag1 and Rag2 gene expression in CD4+CD8+ double-positive (DP) thymocytes depends on the activity of a distant anti-silencer element (ASE) that counteracts the activity of an intergenic silencer. However, the mechanistic basis for ASE activity is unknown. Here, we show that the ASE physically interacts with the distant Rag1 and Rag2 gene promoters in DP thymocytes, bringing the two promoters together to form an active chromatin hub. Moreover, we show that the ASE functions as a classical enhancer that can potently activate these promoters in the absence of the silencer or other locus elements.
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7

Klemm, Lars, Srividya Swaminathan, Elli Papaemmanuil, et al. "Exposure to Inflammatory Immune Responses As Driver of Clonal Evolution in Childhood Acute Lymphoblastic Leukemia." Blood 126, no. 23 (2015): 166. http://dx.doi.org/10.1182/blood.v126.23.166.166.

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Abstract Background: Pediatric pre-B acute lymphoblastic leukemia (ALL) may develop from prenatal chromosomal translocations acquired in utero. For instance, the ETV6-RUNX1 gene rearrangement (~25% of childhood ALL) is found in the umbilical cord blood and Guthrie blood spots of 1 in 100 healthy newborns, however, only 1 in 14,000 carriers develop overt leukemia. The molecular mechanisms driving clonal evolution towards overt leukemia were not clear. Rationale: Activation Induced Cytidine Deaminase (AID) and Recombination Activation Genes 1 and 2 (RAG1-RAG2) are genetic modifiers of the immuno
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8

Swaminathan, Srividya, Lars Klemm, Eugene Park, et al. "Mechanisms of Clonal Evolution of Pre-Leukemic Clones in Childhood Pre-B Acute Lymphoblastic Leukemia." Blood 124, no. 21 (2014): 861. http://dx.doi.org/10.1182/blood.v124.21.861.861.

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Abstract Background and hypothesis: Childhood pre-B acute lymphoblastic leukemia (ALL) can frequently be retraced to a pre-leukemic clone carrying a prenatally acquired genetic lesion (e.g. ETV6-RUNX1gene rearrangement). After birth, pre-leukemic clones can acquire secondary mutations and, hence, evolve towards overt leukemia. While this concept is well established, the mechanism(s) driving clonal evolution are not known. Epidemiological findings hint to a role of delayed childhood infections and chronic inflammation as etiologic factors of childhood ALL, but do not illuminate mechanism of clo
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9

Lee, Baeck-seung, Joseph D. Dekker, Bum-kyu Lee, et al. "The BCL11A Transcription Factor Directly Activates RAG Gene Expression and V(D)J Recombination." Molecular and Cellular Biology 33, no. 9 (2013): 1768–81. http://dx.doi.org/10.1128/mcb.00987-12.

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Recombination-activating gene 1 protein (RAG1) and RAG2 are critical enzymes for initiating variable-diversity-joining (VDJ) segment recombination, an essential process for antigen receptor expression and lymphocyte development. The transcription factor BCL11A is required for B cell development, but its molecular function(s) in B cell fate specification and commitment is unknown. We show here that the major B cell isoform, BCL11A-XL, binds the RAG1 promoter and Erag enhancer to activate RAG1 and RAG2 transcription in pre-B cells. We employed BCL11A overexpression with recombination substrates
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10

Bories, JC, JM Cayuela, P. Loiseau, and F. Sigaux. "Expression of human recombination activating genes (RAG1 and RAG2) in neoplastic lymphoid cells: correlation with cell differentiation and antigen receptor expression." Blood 78, no. 8 (1991): 2053–61. http://dx.doi.org/10.1182/blood.v78.8.2053.2053.

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Abstract Regulation of V-(D)-J recombinations that occur in antigen receptor encoding genes remains poorly understood. Recently, two genes, RAG1 and RAG2, that are able to activate rearrangement of synthetic recombination substrates were cloned in mouse and a human gene homologous to RAG1 was described. To define the differentiation stages corresponding to RAG1 and RAG2 RNA expression, we have studied a large number of B- and T-lymphoid neoplasias. First, we show that a human gene homologous to the murine RAG2 is transcribed in humans. Moreover, using a polymerase chain reaction approach, we h
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11

Bories, JC, JM Cayuela, P. Loiseau, and F. Sigaux. "Expression of human recombination activating genes (RAG1 and RAG2) in neoplastic lymphoid cells: correlation with cell differentiation and antigen receptor expression." Blood 78, no. 8 (1991): 2053–61. http://dx.doi.org/10.1182/blood.v78.8.2053.bloodjournal7882053.

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Regulation of V-(D)-J recombinations that occur in antigen receptor encoding genes remains poorly understood. Recently, two genes, RAG1 and RAG2, that are able to activate rearrangement of synthetic recombination substrates were cloned in mouse and a human gene homologous to RAG1 was described. To define the differentiation stages corresponding to RAG1 and RAG2 RNA expression, we have studied a large number of B- and T-lymphoid neoplasias. First, we show that a human gene homologous to the murine RAG2 is transcribed in humans. Moreover, using a polymerase chain reaction approach, we have shown
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12

Malshetty, Vidyasagar, Jian Chen, Mary Hanna, and Patricia Cortes. "Role of Pax5 and YY1 in regulation of V(D)J recombination (111.1)." Journal of Immunology 188, no. 1_Supplement (2012): 111.1. http://dx.doi.org/10.4049/jimmunol.188.supp.111.1.

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Abstract The infinite variety of antigen-binding receptors originates from the rearrangement of B and T-cell receptor loci in a process known as V(D)J recombination. The initial site-specific DNA cleavage steps of this process are catalyzed by the lymphoid specific proteins RAG1 and RAG2. Deregulation of this process, leads to a spectrum of diseases including immunodeficiency and leukemia. These leukemias are believed to arise from RAG1/2 mediated oncogenic chromosomal translocations. The transcription factor Pax5 is critical for B cell development and is known that, it interacts with RAG1/2 a
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13

Swaminathan, Srividya, Lars Klemm, Anthony M. Ford, et al. "Cooperation Between Aid and the Rag1/Rag2 V(D)J Recombinase Drives Clonal Evolution of Childhood Acute Lymphoblastic Leukemia." Blood 120, no. 21 (2012): 519. http://dx.doi.org/10.1182/blood.v120.21.519.519.

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Abstract Abstract 519 Background and Rationale: In many cases, childhood acute lymphoblastic leukemia (ALL) can be retraced to a recurrent genetic lesion in utero which establishes a pre-leukemic clone. The TEL-AML1 fusion gene for instance, arises prenatally and defines the most frequent subtype of childhood ALL. Strikingly, ∼1 of 100 healthy newborns carry a TEL-AML1 pre-leukemic clone, but only less than 1% of these children eventually develop leukemia. Encounter of infectious antigen leads to activation of the mutator enzyme AID in mature B cells. While AID is required for somatic hypermut
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14

Schabla, N. Max, and Patrick C. Swanson. "The CRL4VPRBP(DCAF1) E3 ubiquitin ligase directs constitutive RAG1 degradation in a non-lymphoid cell line." PLOS ONE 16, no. 10 (2021): e0258683. http://dx.doi.org/10.1371/journal.pone.0258683.

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The development of B and T lymphocytes critically depends on RAG1/2 endonuclease activity to mediate antigen receptor gene assembly by V(D)J recombination. Although control of RAG1/2 activity through cell cycle- and ubiquitin-dependent degradation of RAG2 has been studied in detail, relatively little is known about mechanisms regulating RAG1 stability. We recently demonstrated that VprBP/DCAF1, a substrate adaptor for the CRL4 E3 ubiquitin ligase complex, is required to maintain physiological levels of RAG1 protein in murine B cells by facilitating RAG1 turnover. Loss of VprBP/DCAF1 in vivo re
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15

Schabla, N. Max, and Patrick C. Swanson. "The CRL4VPRBP(DCAF1) E3 ubiquitin ligase directs constitutive RAG1 degradation in a non-lymphoid cell line." PLOS ONE 16, no. 10 (2021): e0258683. http://dx.doi.org/10.1371/journal.pone.0258683.

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The development of B and T lymphocytes critically depends on RAG1/2 endonuclease activity to mediate antigen receptor gene assembly by V(D)J recombination. Although control of RAG1/2 activity through cell cycle- and ubiquitin-dependent degradation of RAG2 has been studied in detail, relatively little is known about mechanisms regulating RAG1 stability. We recently demonstrated that VprBP/DCAF1, a substrate adaptor for the CRL4 E3 ubiquitin ligase complex, is required to maintain physiological levels of RAG1 protein in murine B cells by facilitating RAG1 turnover. Loss of VprBP/DCAF1 in vivo re
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16

Lassoued, Kaiss, Vincent Fuentes, Hussein Gamlouch та ін. "Role of the MAPK and PI3-Kinase/Akt Pathways in the Pre-B Cell Receptor (pre-BCR)-Induced NF-κb Activation and Rag1 and Rag2 Down Regulation." Blood 114, № 22 (2009): 2667. http://dx.doi.org/10.1182/blood.v114.22.2667.2667.

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Abstract Abstract 2667 Poster Board II-643 The pre-BCR acts as a critical checkpoint in pre-B cell development and might be also involved in leukemogenesis. Using the 697 and Nalm6 human pre-B cell lines, we have previously shown that pre-BCR stimulation resulted in cell cycle progression associated with activation of number of adaptors and signaling pathways including the PI3-Kinase/Akt, Ras/MAPK, AP1 and the canonical NFkB pathway. We have also demonstrated that Src kinases together with Syk played a crucial role in controlling the pre-BCR-associated functions, acting upstream the above-ment
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Kuwata, Naomi, Hideya Igarashi, Takafumi Ohmura, Shinichi Aizawa, and Nobuo Sakaguchi. "Cutting Edge: Absence of Expression of RAG1 in Peritoneal B-1 Cells Detected by Knocking into RAG1 Locus with Green Fluorescent Protein Gene." Journal of Immunology 163, no. 12 (1999): 6355–59. http://dx.doi.org/10.4049/jimmunol.163.12.6355.

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Abstract It has been proposed that Ig gene rearrangement in the peritoneal cavity (Pc) B-1 cells might be involved in autoantibody generation. To study possible secondary B cell maturation, we prepared mice carrying a target integration of gfp gene into a rag1 locus (rag1/gfp mice). The GFP+ cells express rag1 mRNA and are undergoing Ig gene rearrangement. RAG1 expression was studied in Pc B-1 cells to detect cells during the stage of Ig gene rearrangement. In contrast to previous reports, Pc B-1 cells did not show RAG1 expression in adolescent or elderly mice. RAG1 expression was not induced
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18

Meru, Nadine, Andreas Jung, Irith Baumann, and Gerald Niedobitek. "Expression of the recombination-activating genes in extrafollicular lymphocytes but no apparent reinduction in germinal center reactions in human tonsils." Blood 99, no. 2 (2002): 531–37. http://dx.doi.org/10.1182/blood.v99.2.531.

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Abstract V(D)J recombination in lymphocytes is mediated by 2 recombination-activating genes, RAG1 and RAG2,which are expressed during lymphocyte development in bone marrow and thymus. Prompted by studies reporting re-expression of the RAGs in germinal center B cells, the expression of RAGs and terminal deoxynucleotidyl transferase (TdT) in human lymphoid tissues was examined using in situ hybridization and immunohistochemistry, respectively. Here it is shown that RAGs and TdT are not reinduced in germinal center reactions. However, RAG+/TdT+ cells are frequently present in extrafollicular area
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Miot, Charline, Rahul Arya, Thomas Burn, Edward M. Behrens, and Craig Bassing. "Elucidating roles of the Rag1 N-terminus and RAG DSBs in shaping the cellular response to TCRa recombination." Journal of Immunology 204, no. 1_Supplement (2020): 80.8. http://dx.doi.org/10.4049/jimmunol.204.supp.80.8.

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Abstract The RAG1/RAG2 (RAG) endonuclease generates lymphocyte antigen receptor gene diversity via V(D)J recombination. The large numbers of V, D, and J segments and inherent imprecision in repair of RAG DNA double strand breaks (DSBs) together establish a vast diversity of antigen receptor specificities, including self-reactive receptors. Mechanisms have evolved to negatively select self-reactive cells and inhibit autoimmunity. In humans, deletion of the RAG1 N-terminus causes Omenn Syndrome, a fatal immunodeficiency with ab T cell-based autoimmunity. We discovered impaired negative selection
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Luo, Gerald Y. "Comparison Study on the Effects of Adaptive Immune Deficiency on Liver Morphology and ApoE Gene Expression in Mice Fed a High-Fat Diet." Theoretical and Natural Science 126, no. 1 (2025): 30–36. https://doi.org/10.54254/2753-8818/2025.au25062.

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This study investigated the effects of adaptive immune deficiency (achieved by Rag1 gene knockout, Rag1-/-) on metabolic disorders induced by high-fat diet in mice, especially liver changes and apolipoprotein E (ApoE) expression. Wild-type (Wt) C57BL/6J mice and Rag1-/-mice were randomly divided into normal diet group and high-fat diet group and fed for 8 weeks. The results showed that high-fat diet significantly increased the liver weight of Wt and Rag1-/-mice and downregulated the expression of ApoE mRNA in the liver. Although not significant, the increase in body weight and liver weight cau
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21

Shaw, Albert C., Wojciech Swat, Roger Ferrini, Laurie Davidson, and Frederick W. Alt. "Activated Ras Signals Developmental Progression of Recombinase-activating Gene (RAG)-deficient Pro-B Lymphocytes." Journal of Experimental Medicine 189, no. 1 (1999): 123–29. http://dx.doi.org/10.1084/jem.189.1.123.

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To elucidate the intracellular pathways that mediate early B cell development, we directed expression of activated Ras to the B cell lineage in the context of the recombination-activating gene 1 (RAG1)-deficient background (referred to as Ras–RAG). Similar to the effects of an immunoglobulin (Ig) μ heavy chain (HC) transgene, activated Ras caused progression of RAG1–deficient progenitor (pro)-B cells to cells that shared many characteristics with precursor (pre)-B cells, including downregulation of surface CD43 expression plus expression of λ5, RAG2, and germline κ locus transcripts. However,
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Igarashi, Hideya, Naomi Kuwata, Kumiko Kiyota, et al. "Localization of recombination activating gene 1/green fluorescent protein (RAG1/GFP) expression in secondary lymphoid organs after immunization with T-dependent antigens in rag1/gfpknockin mice." Blood 97, no. 9 (2001): 2680–87. http://dx.doi.org/10.1182/blood.v97.9.2680.

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Abstract Secondary rearrangements of immunoglobulin gene segments that generate a new antibody repertoire in peripheral B cells have been described as receptor revision and occur by as yet unknown mechanisms. To determine the importance of recombination activating gene (RAG) expression in receptor revision, heterozygous rag1/green fluorescent protein (gfp) knockin mice were used to examine the location of RAG1 expression in the germinal centers (GCs) of lymphoid follicles after immunization with a variety of T-cell–dependent antigens. Immunization of rag1/gfp heterozygous mice orrag1 homozygou
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23

Carroll, Virginia A., Mark K. Lafferty, Luigi Marchionni, Joseph L. Bryant, Robert C. Gallo, and Alfredo Garzino-Demo. "Expression of HIV-1 matrix protein p17 and association with B-cell lymphoma in HIV-1 transgenic mice." Proceedings of the National Academy of Sciences 113, no. 46 (2016): 13168–73. http://dx.doi.org/10.1073/pnas.1615258113.

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HIV-1 infection is associated with increased risk for B-cell lymphomas. How HIV infection promotes the development of lymphoma is unclear, but it may involve chronic B-cell activation, inflammation, and/or impaired immunity, possibly leading to a loss of control of oncogenic viruses and reduced tumor immunosurveillance. We hypothesized that HIV structural proteins may contribute to lymphomagenesis directly, because they can persist long term in lymph nodes in the absence of viral replication. The HIV-1 transgenic mouse Tg26 carries a noninfectious HIV-1 provirus lacking part of the gag-pol reg
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Muire, Preeti Judith, Larry Hanson, Jeffrey Yoder, and Lora Petrie-Hanson. "Transcript analysis of natural killer (NK) cell specific genes in the liver, kidney and spleen tissues of rag1 −/− mutant zebrafish in response to in vivo administration of TLR ligands." Journal of Immunology 196, no. 1_Supplement (2016): 216.4. http://dx.doi.org/10.4049/jimmunol.196.supp.216.4.

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Abstract T and B cells mediate specific protective immunity. NK cells can also mediate a memory response to murine cytomegalovirus in T and B cell deficient rag2−/− mice. T and B cell deficient rag1−/− mutant zebrafish mediate protective immunity to intracellular bacteria. NK cells have not been characterized in zebrafish due to a lack of tools to target specific markers. The aim of this study was to evaluate NK cell tissue distribution and transcript response to TLR ligands in rag1−/− mutant zebrafish. We accomplished this by determining the level of expression of ifnγ, t-bet, nitr9, and NK l
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25

Xu, Mei, Brenda Reid, and Chaim M. Roifman. "Identification of a novel RAG1 hypomorphic mutation in a child presenting with disseminated vaccine-strain varicella." LymphoSign Journal 8, no. 1 (2021): 5–10. http://dx.doi.org/10.14785/lymphosign-2021-0014.

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Background: Recombination-activating gene 1 (RAG1) and recombination-activating gene 2 (RAG2) encode unique lymphocyte endonuclease proteins that are crucial in T and B cell development through V(D)J recombination. RAG1 gene defects lead to variable phenotypes, ranging from immunocompetent to severe combined immunodeficiency (SCID). Curative therapy for severe manifestations can be achieved through hematopoietic stem cell transplantation (HSCT). Advances in genomic sequencing have led to the discovery of new variants and it is recognized that the level of recombinase activity correlates with d
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Dolence, Joseph J., Kimberly Gwin, and Kay L. Medina. "Haploinsufficiency of Flt3-ligand limits RAG1 locus activation (87.2)." Journal of Immunology 182, no. 1_Supplement (2009): 87.2. http://dx.doi.org/10.4049/jimmunol.182.supp.87.2.

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Abstract Evidence is accumulating that the molecular circuitry initiating lymphoid lineage specification correlates with expression of the receptor tyrosine kinase Flt3. Recombination activating gene-1 (RAG1) locus activation is a hallmark of lymphoid lineage specification. Previous studies established that expression of a RAG1-GFP/+ reporter begins in a subset of lineage negative (Lin-) cells that express high levels of c-kit and Sca-1 (LSK+). To investigate a regulatory connection between Flt3 signaling and RAG1 locus activation from this stage, RAG1-GFP/+ knockin mice expressing wildtype, h
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27

Schabla, N. Max, Greg A. Perry, Victoria L. Palmer, and Patrick C. Swanson. "VprBP (DCAF1) Regulates RAG1 Expression Independently of Dicer by Mediating RAG1 Degradation." Journal of Immunology 201, no. 3 (2018): 930–39. http://dx.doi.org/10.4049/jimmunol.1800054.

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Pike-Overzet, Karin, Christopher Baum, Robbert G. M. Bredius, et al. "Successful RAG1-SCID gene therapy depends on the level of RAG1 expression." Journal of Allergy and Clinical Immunology 134, no. 1 (2014): 242–43. http://dx.doi.org/10.1016/j.jaci.2014.04.033.

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Galler, Gunther R., Cornelia Mundt, Mathew Parker, Roberta Pelanda, Inga-Lill Mårtensson та Thomas H. Winkler. "Surface μ Heavy Chain Signals Down-Regulation of the V(D)J-Recombinase Machinery in the Absence of Surrogate Light Chain Components". Journal of Experimental Medicine 199, № 11 (2004): 1523–32. http://dx.doi.org/10.1084/jem.20031523.

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Early B cell development is characterized by stepwise, ordered rearrangement of the immunoglobulin (Ig) heavy (HC) and light (LC) chain genes. Only one of the two alleles of these genes is used to produce a receptor, a phenomenon referred to as allelic exclusion. It has been suggested that pre–B cell receptor (pre-BCR) signals are responsible for down-regulation of the VDJH-recombinase machinery (Rag1, Rag2, and terminal deoxynucleotidyl transferase [TdT]), thereby preventing further rearrangement on the second HC allele. Using a mouse model, we show that expression of an inducible μHC transge
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Hauer, Julia, Charles Mullighan, Estelle Morillon, et al. "Loss of p19Arf in a Rag1−/− B-cell precursor population initiates acute B-lymphoblastic leukemia." Blood 118, no. 3 (2011): 544–53. http://dx.doi.org/10.1182/blood-2010-09-305383.

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Abstract In human B-acute lymphoblastic leukemia (B-ALL), RAG1-induced genomic alterations are important for disease progression. However, given that biallelic loss of the RAG1 locus is observed in a subset of cases, RAG1's role in the development of B-ALL remains unclear. We chose a p19Arf−/−Rag1−/− mouse model to confirm the previously published results concerning the contribution of CDKN2A (p19ARF /INK4a) and RAG1 copy number alterations in precursor B cells to the initiation and/or progression to B-acute lymphoblastic leukemia (B-ALL). In this murine model, we identified a new, Rag1-indepe
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Han, S., B. Zheng, D. G. Schatz, E. Spanopoulou, and G. Kelsoe. "Neoteny in Lymphocytes: Rag1 and Rag2 Expression in Germinal Center B Cells." Science 274, no. 5295 (1996): 2094–97. http://dx.doi.org/10.1126/science.274.5295.2094.

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Yokota, Takafumi, Kenji Oritani, Stefan Butz, et al. "The Endothelial Antigen ESAM Marks Hematopoietic Stem Cells throughout Life." Blood 112, no. 11 (2008): 727. http://dx.doi.org/10.1182/blood.v112.11.727.727.

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Abstract Hematopoietic stem cells (HSC) are an important cell type with the capacity for self-renewal as well as differentiation into multi-lineage blood cells, maintaining the immune system throughout life. Many studies have attempted to identify unique markers associated with these extremely rare cells. In bone marrow of adult mice, the Lin-c-kitHi Sca1+ CD34−/Lo Thy1.1Lo subset is known to include HSC with long-term repopulating capacity. However, several of these parameters differ between strains of mice, change dramatically during developmental age and/or are expressed on many non-HSC dur
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33

Anbazhagan, Kolandaswamy, Vincent Fuentes, Eliane Bissac, et al. "The Human Pre-B Cell Receptor Signaling Cascade Is Regulated Via PI-3Kinase and MAPK Pathway." Blood 118, no. 21 (2011): 1314. http://dx.doi.org/10.1182/blood.v118.21.1314.1314.

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Abstract Abstract 1314 Background: Pre-B cell receptor (pre-BCR) constitutes a major check point in the early steps of mouse and human B cell development. Several functions have been attributed to this receptor which include a delivery of proliferation and survival signals, increased sensitivity to interleukin-7 (IL-7) and down modulation of recombinase activating genes (RAG) and surrogate light chain (SLC) encoding genes. Pre-BCR is also involved in shaping the VH repertoire and preventing autoimmunity. Finally, there is increasing evidence that pre-BCR might be implicated in leukemogenesis.
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34

Yoshikawa, Genki, Kazuko Miyazaki, Hiroyuki Ogata, and Masaki Miyazaki. "The Evolution of Rag Gene Enhancers and Transcription Factor E and Id Proteins in the Adaptive Immune System." International Journal of Molecular Sciences 22, no. 11 (2021): 5888. http://dx.doi.org/10.3390/ijms22115888.

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Adaptive immunity relies on the V(D)J DNA recombination of immunoglobulin (Ig) and T cell receptor (TCR) genes, which enables the recognition of highly diverse antigens and the elicitation of antigen-specific immune responses. This process is mediated by recombination-activating gene (Rag) 1 and Rag2 (Rag1/2), whose expression is strictly controlled in a cell type-specific manner; the expression of Rag1/2 genes represents a hallmark of lymphoid lineage commitment. Although Rag genes are known to be evolutionally conserved among jawed vertebrates, how Rag genes are regulated by lineage-specific
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35

Niebergall, Emily R., Emily A. Beck, Susan Bassham, and William A. Cresko. "Advancing threespine stickleback as an outbred immunogenetics model by pinpointing the onset of adaptive immunity." Journal of Immunology 202, no. 1_Supplement (2019): 53.25. http://dx.doi.org/10.4049/jimmunol.202.supp.53.25.

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Abstract The development of an outbred immunogenetics model system is needed to understand how genetic variation impacts phenotypic variation of disease states in humans. Threespine stickleback fish (Gasterosteus aculeatus) provide just such a model. Stickleback are genetically tractable laboratory organisms with a well-annotated genome, but with lines drawn from populations inhabiting vastly different habitats. Individuals from different populations show high levels of genetic variation. The onset of the adaptive immune system is currently unknown in stickleback, a significant hindrance in st
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36

Willett, Catherine E., Jason J. Cherry, and Lisa A. Steiner. "Characterization and expression of the recombination activating genes (rag1 and rag2) of zebrafish." Immunogenetics 45, no. 6 (1997): 394–404. http://dx.doi.org/10.1007/s002510050221.

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Jain, Pooja, Rashida Ginwala, Paige Charlins та ін. "HTLV-1 infection and neuropathogenesis in the context of Rag1−/−γc−/− (RAG1) and BLT mice". Journal of Immunology 196, № 1_Supplement (2016): 217.30. http://dx.doi.org/10.4049/jimmunol.196.supp.217.30.

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Abstract HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a disabling chronic inflammatory disease of the central nervous system (CNS) with similarities to multiple sclerosis (MS). To date, the lack of a suitable small animal model has hindered our quest to understand the immuno- and neuropathogenesis of HTLV-1 in an in vivo system. Previous work from others have established that host immune response plays a critical role in the outcome of HTLV-1 infection, which could be better tested in the context of humanized (hu) mice. Thus, we employ here the Rag1 as well as Bone ma
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38

Dangoudoubiyam, Sriveny, Ramesh Vemulapalli, Kathy Hancock, and Kevin R. Kazacos. "Molecular Cloning of an Immunogenic Protein of Baylisascaris procyonis and Expression in Escherichia coli for Use in Developing Improved Serodiagnostic Assays." Clinical and Vaccine Immunology 17, no. 12 (2010): 1933–39. http://dx.doi.org/10.1128/cvi.00404-10.

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ABSTRACT Larva migrans caused by Baylisascaris procyonis is an important zoonotic disease. Current serological diagnostic assays for this disease depend on the use of the parasite's larval excretory-secretory (ES) antigens. In order to identify genes encoding ES antigens and to generate recombinant antigens for use in diagnostic assays, construction and immunoscreening of a B. procyonis third-stage larva cDNA expression library was performed and resulted in identification of a partial-length cDNA clone encoding an ES antigen, designated repeat antigen 1 (RAG1). The full-length rag1 cDNA contai
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39

Madagula, Kiran Kumar, Rashida Ginwala, Breanna Caruso та ін. "HTLV-1 infection and neuropathogenesis in the context of Rag1−/−γc−/− (RAG1-hu) and BLT mice". Journal of Immunology 198, № 1_Supplement (2017): 78.29. http://dx.doi.org/10.4049/jimmunol.198.supp.78.29.

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Abstract To date, the lack of a suitable small animal model has hindered our quest to understand the immuno- and neuropathogenesis of HTLV-1, the causative agent of chronic disabling neuroinflammatory disease HAM/TSP. Host immune response that plays a critical role in the outcome of HTLV-1 infection could be better tested in the context of humanized (hu) mice. Thus, we infected neonatal and adult Balb/c-Rag1−/−γc−/− (Rag1) as well as Bone marrow-Liver-Thymic (BLT) mice with HTLV-1. Proviral load (PVL) was determined in the peripheral blood, spleen, and other organs by droplet digital PCR. With
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40

Glynn, Rebecca, and Craig Bassing. "Elucidating the Role of NEMO and SpiC in DNA Double Strand Break Induced Inhibition of V(D)J Recombination." Journal of Immunology 204, no. 1_Supplement (2020): 223.12. http://dx.doi.org/10.4049/jimmunol.204.supp.223.12.

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Abstract V(D)J recombination is regulated such that most lymphocytes assemble and express an antigen receptor from only one allele (allelic exclusion). In pre-B cells, RAG-induced DNA double strand breaks (DSBs) at Igκ loci signal via ATM to rapidly repress Rag1/2 transcription, inhibit accessibility of Igk loci, and limit V recombination. We hypothesize that RAG DSB-induced repression of Rag1/2 is critical to transiently limit V recombination, ensure allelic exclusion, and inhibit oncogenic Ig translocations. Fittingly, Atm−/− mice have higher frequencies of developing B cells with RAG DSBs a
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41

Kurtz, Courtney C., Ioannis Drygiannakis, Makoto Naganuma, et al. "Extracellular adenosine regulates colitis through effects on lymphoid and nonlymphoid cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 307, no. 3 (2014): G338—G346. http://dx.doi.org/10.1152/ajpgi.00404.2013.

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Adenosine is a purine metabolite that can mediate anti-inflammatory responses in the digestive tract through the A2A adenosine receptor (A2AAR). We examined the role of this receptor in the control of inflammation in the adoptive transfer model of colitis. Infection of A2AAR−/− mice with Helicobacter hepaticus increased colonic inflammation scores compared with uninfected A2AAR controls. Comparison of T cell subsets in wild-type and A2AAR−/− mice revealed differences in markers associated with activated helper T (Th) cells and regulatory T (Treg) cells. Previous studies showed that expression
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42

Jarvelainen, Harri, Wei-Hsiang Lin, Moorim Kang, Xiaojie Zhou, Robert F. Place, and Long-Cheng Li. "Preclinical development of RAG1-40-31L: A novel small activating RNA-lipid conjugate targeting tumor suppressor gene p21 for treatment of non-muscle invasive bladder cancer." Journal of Clinical Oncology 41, no. 16_suppl (2023): e16620-e16620. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e16620.

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e16620 Background: Loss-of-function of tumor suppressor genes are the dominant driving force in tumorigenesis. Restoration in function and/or expression of these genes holds tremendous therapeutic potential in cancer treatment. Bladder cancer is the 9th leading cause of cancer-related deaths in the United States in which ~75% of all newly diagnosed cases are non-muscle invasive bladder cancer (NMIBC). Standard-of-care includes intravesical installation of Bacillus Calmette-Guerin following tumor resection with an expected failure rate of ~50% within 6 months for patients with high-grade tumors
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43

Girschick, Hermann J., Amrie C. Grammer, Toshihiro Nanki, Marlyn Mayo, and Peter E. Lipsky. "RAG1 and RAG2 Expression by B Cell Subsets from Human Tonsil and Peripheral Blood." Journal of Immunology 166, no. 1 (2001): 377–86. http://dx.doi.org/10.4049/jimmunol.166.1.377.

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44

Lynch, Sara, Dermot Kelleher, Ross McManus, and Cliona O'Farrelly. "RAG1 and RAG2 expression in human intestinal epithelium: evidence of extrathymic T cell differentiation." European Journal of Immunology 25, no. 5 (1995): 1143–47. http://dx.doi.org/10.1002/eji.1830250502.

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45

Auer, Franziska, Deborah Ingenhag, Isidro Sánchez-García, Arndt Borkhardt, and Julia Hauer. "Activation Induced Cytidine Deaminase (Aid) Acts As a Gate Keeper in Pro-B Cells and Prevents PB-ALL." Blood 128, no. 22 (2016): 1538. http://dx.doi.org/10.1182/blood.v128.22.1538.1538.

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Abstract Introduction: Activation induced cytidine deaminase (AID) mediates somatic hypermutation and class switch recombination in splenic germinal center B cells and is implicated in retaining central B cell tolerance in the bone marrow (BM) (Cantaert et al., Immunity, 2015). Moreover, there is recent in vitro evidence that AID is upregulated in precursor B cells after exposure to LPS, contributing to the clonal evolution of pB-ALL (Swaminathan et al., Nat Immunol, 2015) (Greaves M. and Müschen M., Cancer Discovery, 2015). These studies were carried out in pre-BII / early immature B cells, w
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46

Sacramento, Lais A., Camila Farias Amorim, Claudia Lombana, and Phillip Scott. "CD8 +T cells require CCR5 expression to mediate immunopathology in cutaneous leishmaniasis." Journal of Immunology 210, no. 1_Supplement (2023): 81.15. http://dx.doi.org/10.4049/jimmunol.210.supp.81.15.

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Abstract Cytolytic CD8 +T cells mediate immunopathology in cutaneous leishmaniasis by a mechanism dependent on degranulation and lysis of Leishmania-infected cells, culminating in NLRP3 activation and IL-1b release. Here, we sought to identify chemokine receptors involved in CD8 +T cell migration to the lesion that could be employed as a treatment target to ameliorate disease severity. A transcriptional study identified the profile of chemokine receptors that predicts treatment failure in Leishmania braziliensispatients and identifies possible targets that may be involved in CD8 +T cell migrat
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Koulnis, Miro, Ying Liu, and Merav Socolovsky. "Negative Autoregulation by Fas Stabilizes the Erythroid Progenitor Pool and Accelerates the Erythropoietic Stress Response." Blood 116, no. 21 (2010): 2045. http://dx.doi.org/10.1182/blood.v116.21.2045.2045.

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Abstract Abstract 2045 Signaling and transcriptional networks frequently contain negative autoregulatory feedback loops, where gene products negatively regulate their own induction or activation. These negative autoregulatory motifs are predicted to exert dual functions, accelerating gene induction, and providing stable gene expression levels in the face of the random perturbations inherent to biological systems. These predictions were confirmed experimentally in synthetic transcriptional circuits [1,2], but it is unknown whether they also hold in naturally occurring higher level biological ne
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Vaitaitis, Gisela, and David Wagner. "CD40 induced TCR revision promotes tolerance to self-antigen in Type I Diabetes pathogenic CD4+CD40+ T cells. (176.11)." Journal of Immunology 188, no. 1_Supplement (2012): 176.11. http://dx.doi.org/10.4049/jimmunol.188.supp.176.11.

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Abstract Biomarkers for effector cells have been difficult to find, but we described a pathogenic CD4 T cell subset expressing CD40. We demonstrated that peripheral CD4+CD40+ T cells are necessary and sufficient to transfer autoimmune disease. Here we demonstrate that CD40 engagement of peripheral CD4+CD40+ T cells in-vitro renders those cells unable to transfer disease. We have shown that CD40 signals primary peripheral CD4+CD40+ T cells to access the recombination machinery that causes revision of TCR Vα. We demonstrate here that CD40 signals also causes revision of TCR Vβ. While this consti
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Sathe, Priyanka, David Vremec, Li Wu, Lynn Corcoran, and Ken Shortman. "Convergent differentiation: myeloid and lymphoid pathways to murine plasmacytoid dendritic cells." Blood 121, no. 1 (2013): 11–19. http://dx.doi.org/10.1182/blood-2012-02-413336.

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Abstract The developmental origin of IFN-producing plasmacytoid dendritic cells (pDCs) has been uncertain. In the present study, we tracked the development of pDCs in cultures of BM precursors stimulated with Flt3 ligand. Common myeloid precursors (CMPs) produced both conventional DCs (cDCs) and pDCs via the DC-restricted common DC precursor. Common lymphoid precursors (CLPs) produced only a few cDCs with variable efficiency, but produced pDCs via a transient intermediate precursor with B-cell potential. The pDCs of both origins produced IFN-α when stimulated with CpG oligonucleotides. The pDC
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Düber, Sandra, Martin Hafner, Martina Krey, et al. "Induction of B-cell development in adult mice reveals the ability of bone marrow to produce B-1a cells." Blood 114, no. 24 (2009): 4960–67. http://dx.doi.org/10.1182/blood-2009-04-218156.

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Abstract To study B-cell development from bone marrow (BM), we generated recombination-activating gene 1 (Rag1)–targeted mice lacking mature lymphocytes. B-cell development can be induced in such mice by B cell–specific restoration of a functional Rag1 transcription unit. Follicular and marginal zone B cells populated the spleen when Rag1 expression was permitted. Notably, the peritoneal cavity was dominated by bona fide B-1a cells, as judged by surface markers and functional properties. These BM-derived B-1a cells exhibited a polyclonal VDJ repertoire with substantial N nucleotide insertions.
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