The Role of Orphan Nuclear Receptor in Thymocyte Differentiation and Lymphoid Organ Development

He, You–Wen

doi:10.1385/ir:22:2-3:71

Cited by 17 publications

(7 citation statements)

References 62 publications

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“…Regulation of Resting DP Thymocyte Phenotype by RORgt RORgt-deficient thymocytes have a high percentage of proliferating cells, poor survival at the DP stage, low expression of Bcl-X L and Rag2, and altered TCR a gene rearrangement (Guo et al, 2002;He, 2000;Sun et al, 2000). These phenotypes could be a direct result of the removal of RORgt or may be secondary to a developmental block.…”

Section: Resultsmentioning

confidence: 99%

Interplay between RORγt, Egr3, and E Proteins Controls Proliferation in Response to Pre-TCR Signals

et al. 2006

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The response of thymocytes to pre-T cell receptor (pre-TCR) signaling includes proliferation and gene rearrangement, two cellular processes that are incompatible. The control of proliferation by pre-TCR signals depends on the activities of the transcription factors RORgammat, Egr3, E12, and E47. Here, we describe a regulatory network in which interplay between these factors ensures transient proliferation that is temporally distinct from gene rearrangement. RORgammat expression was elevated after pre-TCR signaling, and RORgammat promoted gene rearrangement in CD4+, CD8+ cells by inhibiting cell division, promoting survival via Bcl-X(L), and inducing Rag2. Egr3 was transiently induced by pre-TCR signals and promoted a distinct proliferative phase by reducing E protein-dependent RORgammat expression and interacting with RORgammat to prevent induction of target genes. After Egr3 subsided, the expression and function of RORgammat increased. Thus, transient induction of Egr3 delays the effects of RORgammat and enables pre-TCR signaling to induce both proliferation and gene rearrangement.

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Section: Resultsmentioning

confidence: 99%

Interplay between RORγt, Egr3, and E Proteins Controls Proliferation in Response to Pre-TCR Signals

et al. 2006

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“…Several studies have demonstrated that RORγt plays a critical role in the regulation of thymopoiesis [ Guo et al, 2002 ; He, 2000 ; He et al, 1998 ; Hirose et al, 1994 ; Jetten, 2004 ; Jetten and Joo, 2006 ; Kurebayashi et al, 2000 ; Medvedev et al, 1996 ; Ortiz et al, 1995 ; Sun et al, 2000 ]. During thymopoiesis, T cell precursor CD25 - CD44 + CD4 - CD8 - cells (DN1) differentiate successively via two intermediate stages, CD25 + CD44 + (DN2) and CD25 + CD44 - (DN3), into CD44 - CD25 - (DN4) thymocytes ( Figure 5 ).…”

Section: Rors and Developmentmentioning

confidence: 99%

Retinoid-Related Orphan Receptors (RORs): Critical Roles in Development, Immunity, Circadian Rhythm, and Cellular Metabolism

2009

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The last few years have witnessed a rapid increase in our knowledge of the retinoid-related orphan receptors RORα, -β, and -γ (NR1F1-3), their mechanism of action, physiological functions, and their potential role in several pathologies. The characterization of ROR-deficient mice and gene expression profiling in particular have provided great insights into the critical functions of RORs in the regulation of a variety of physiological processes. These studies revealed that RORα plays a critical role in the development of the cerebellum, that both RORα and RORβ are required for the maturation of photoreceptors in the retina, and that RORγ is essential for the development of several secondary lymphoid tissues, including lymph nodes. RORs have been further implicated in the regulation of various metabolic pathways, energy homeostasis, and thymopoiesis. Recent studies identified a critical role for RORγ in lineage specification of uncommitted CD4 + T helper cells into Th17 cells. In addition, RORs regulate the expression of several components of the circadian clock and may play a role in integrating the circadian clock and the rhythmic pattern of expression of downstream (metabolic) genes. Study of ROR target genes has provided insights into the mechanisms by which RORs control these processes. Moreover, several reports have presented evidence for a potential role of RORs in several pathologies, including osteoporosis, several autoimmune diseases, asthma, cancer, and obesity, and raised the possibility that RORs may serve as potential targets for chemotherapeutic intervention. ATRA: all-trans retinoic acid; ATXN1: ataxin 1; BMAL1: brain and muscle ARNT-like 1; CaMKIV: calmodulin-dependent kinase IV; ChIP: Chromatin immunoprecipitation; CRX: cone-rod homeobox factor; CRY: cryptochrome; CT: circadian time; Cyp7b1: oxysterol 7alpha-hydroxylase; DBD: DNA-binding domain; DBP: D site-binding protein; DHR3: Drosophila hormone receptor 3; DKO: double knockout; DP: double positive; EAE: experimental autoimmune encephalomyelitis; EGR: early growth response gene; FOXP3: forkhead box transcription factor p3; HDAC: histone deacetylase; HDL: high density lipoprotein; HIF1α: hypoxia-inducible factor α; IL: interleukin; IRF4: interferon regulatory factor 4; ISP: immature single positive; LBD: ligand binding domain; LPS: lipopolysaccharide; LTi: lymphoid tissue inducer cells; LXR: liver X receptor; NCOA: nuclear receptor coactivator; NCOR: nuclear receptor corepressor; NK: natural killer; Obfc2a: oligonucleotide/oligosaccharide-binding fold-containing 2a; Opn: opsin; OVA: ovalbumin; PER: period protein; PGC-1: peroxisome proliferator-activated receptors coactivator; PND: postnatal day; PPAR: peroxisome proliferators-activated receptor; PPs: Peyer's patches; RAR: retinoic acid receptor; RIP140: receptor-interacting protein 140; ROR: RAR-or retinoid-related orphan receptor; RORE: ROR response element; RUNX1: runt-related transcription factor 1; RXR: retinoid X receptor; sg: staggerer; SCA1: spinocerebellar ataxia type 1; SCN: suprachia...

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“…RORγt is an isoform of the RORγ gene that is expressed predominantly in DP thymocytes. RORγ -/-mice display decreased ISP to DP differentiation, an inability of DP thymocytes to withdraw from cell cycle, and insufficient Tcrα recombination due to a failure of DP thymocytes to up-regulate both Rag2 and Bcl-xL expression (Guo et al, 2002;He, 2000;Sun et al, 2000;Yu et al, 2004). These findings are consistent with an anti-proliferative role of RORγt during the DP stage of T cell development to enable efficient Tcrα recombination.…”

Section: Becoming a Dp Thymocytesupporting

confidence: 60%

c-Myb Regulates the Survival of CD4+CD8+Double Positive Thymocytes

Yuan

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The peripheral T cell repertoire is selected during the CD4 + CD8+ double positive (DP) stage of T cell development for optimized pathogen recognition while maintaining selftolerance. Bcl2l1 encodes the survival factor Bcl-xL, which is specifically upregulated in DP thymocytes to prolong the window of time available for Tcrα rearrangements and the generation of a diverse T cell repertoire. However, despite the importance of Bcl2l1 during T cell development, the regulation of its expression remains poorly understood.The Myb proto-oncogene encodes an essential transcription factor that plays critical roles during several stages of T cell development including DN to DP thymocyte development, DP thymocyte survival and the development of CD4SP thymocytes. Work in this thesis demonstrates that Myb mRNA expression is specifically upregulated in the small, preselection DP stage during T cell development. Using a conditional deletion model in which deletion at the Myb locus takes place in DP thymocytes, we demonstrate that Myb deficient DP thymocytes undergo premature apoptosis, resulting in a limited Tcrα repertoire biased towards 5' Jα segment usage. Premature apoptosis occurs in an αβ-TCR independent manner and is a consequence of decreased Bcl-xL expression. Reintroduction of c-Myb restores both Bcl-xL expression and the small pre-selection DP

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The Role of Orphan Nuclear Receptor in Thymocyte Differentiation and Lymphoid Organ Development

Cited by 17 publications

References 62 publications

Interplay between RORγt, Egr3, and E Proteins Controls Proliferation in Response to Pre-TCR Signals

Interplay between RORγt, Egr3, and E Proteins Controls Proliferation in Response to Pre-TCR Signals

Retinoid-Related Orphan Receptors (RORs): Critical Roles in Development, Immunity, Circadian Rhythm, and Cellular Metabolism

c-Myb Regulates the Survival of CD4+CD8+Double Positive Thymocytes

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