Control of Thymocyte Development and Rag Expression by Zfp608

Zfp608 对胸腺细胞发育和 Rag 表达的控制

• 批准号: 7895604
• 负责人: Thomas M. Aune
• 金额: $ 38.75万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895604
• 关键词: Accounting; Address; Adult; Antigen Receptors; Antigens; Autoantigens; B-Lymphocytes; Birth; Cells; Chromosomes, Human, Pair 18; Complementary DNA; Congenic Strain; Critical Pathways; Defect; Development; Enzymes; Fetal Development; Gene Expression; Genes; Growth; Homeostasis; Human; Immune; Immune response; Immune system; Immunoglobulins; Lead; Life; Lymphocyte; Maps; Mediating; Modeling; Mus; Mutation; Neonatal; Organ; Peripheral; Process; Production; Property; Proteins; Rag1 Mouse; Receptor Cell; Receptor Gene; Regulation; Repression; Research Proposals; Role; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Thymocyte Development; Thymus Gland; Transcription Repressor/Corepressor; Transfection; V(D)J Recombination; Zinc Fingers; adaptive immunity; body system; fetal; gene repression; in utero; neonate; novel; pathogen; postnatal; premature; prenatal; prevent; response; thymocyte

Antigen receptor gene assembly bygene assembly by T and B lymphocytes is a fundamental aspect of adaptive immunity and is required to generate a diverse repertoire of immunoglobulins and I cell receptors, which recognize virtually any pathogen a species may encounter. The processes involved in the ordered assembly of antigen receptor genes by V(D)J recombination is catalyzed by the RAG-I and RAG-2 enzymes, which are uniquely expressed in precursor T and B lymphocytes. However, the mechanisms controlling Ragi and Rag2 gene expression or ontogeny We developed a congenic strain (ZORI, "Zfp608 over-expressing Rag insufficient") with defects in Ragi and Rag2 expression, thymocyte maturation, and peripheral T cell homeostasis. This mutation maps to a chromosome 18 locus containing a single known gene, Zfp608. In wildtype mice, the Zfp608 gene is highly expressed in neonatal thymus but is extinguished after birth. In contrast, ZORI mice sustain thymocyte expression of Zfp608 throughout life. The ZORI mutation produces a thymocyte-intrinsic developmental defect. Over-expression of Zfp608 in normal thymocytes severely impairs Rag expression, providing an underlying mechanism for the defect in ZORI thymocyte development. Thus, the normal function of Zfp608 may be to prevent Rag expression during prenatal and early postnatal development. Our results raise several questions about the mechanisms of Zfp608 regulation and function that we will address in this research proposal. First, how is Zfp608 regulated during ontogeny and what accounts for defective Zfp608 expression in ZORI mice? Second, we hypothesize that targeted deletion of Zfp608 may Rag of to development of the immune aims are I) to examine the role of Zfp608 in thymocyte ontogeny and development, and 2) explore the impact of Zfp608 deficiency on fetal/postnatal development and the adaptive immune response. Project Summary Antigen receptor gene assembly by T and B lymphocytes is a fundamental aspect of adaptive immunity and repertoire immunoglobulins and T recognize virtually The involved 1 uniquely and B lymphocytes. Rag1 during lymphocyte development or mammalian ontogeny are incompletely understood. "Zfp60S over-expressing Rag insufficient") with Rag1 thymocyte maturation, peripheral cell homeostasis. 1S gene, Zfp60S. Zfp60S highly neonatal is extinguished after birth. ZORI mice sustain thymocyte Zfp60S throughout life. The ZORI mutation Zfp60S in normal thymocytes severely impairs Rag expression, providing an underlying for in ZORI thymocyte Zfp60S may be to during prenatal and early postnatal development. questions of Zfp60S will research proposal. Zfp60S regulated Zfp60S Second, we hypothesize that targeted deletion Zfp60S may result in de-repression of Rag genes and premature expansion of T cell subsets, which may provide a model to understand why development of the immune system is delayed in ontogeny compared to development of other organ systems. Our specific aims are 1) to examine the role of Zfp60S in thymocyte ontogeny and development, explore the impact of Zfp60S deficiency on fetal/postnatal development and the adaptive immune

T和B淋巴细胞的抗原受体基因组装是获得性免疫的一个基本方面，并且是产生免疫球蛋白和I细胞受体的多样性库所必需的，所述免疫球蛋白和I细胞受体几乎识别物种可能遇到的任何病原体。参与通过V（D）J重组进行的抗原受体基因有序组装的过程由RAG-1和RAG-2酶催化，RAG-1和RAG-2酶在前体T和B淋巴细胞中独特表达。然而，控制Ragi和Rag 2基因表达或个体发育的机制我们开发了一种在Ragi和Rag 2表达、胸腺细胞成熟和外周T细胞稳态方面具有缺陷的同类菌株（ZORI，“Zfp 608过度表达Rag不足”）。该突变映射到含有单个已知基因Zfp 608的染色体18位点。在野生型小鼠中，Zfp 608基因在新生儿胸腺中高度表达，但在出生后消失。相比之下，ZORI小鼠在整个生命中维持Zfp 608的胸腺细胞表达。ZORI突变会产生胸腺细胞固有的发育缺陷。Zfp 608在正常胸腺细胞中的过表达严重损害Rag表达，为ZORI胸腺细胞发育缺陷提供了潜在机制。因此，Zfp 608的正常功能可能是在产前和出生后早期发育期间阻止Rag表达。我们的研究结果提出了几个关于Zfp 608调控和功能机制的问题，我们将在本研究中解决这些问题。首先，Zfp 608在个体发育过程中是如何调节的，是什么导致了ZORI小鼠中Zfp 608的表达缺陷？其次，我们假设Zfp 608的靶向缺失可能与免疫发育有关，目的是：1）检测Zfp 608在胸腺细胞个体发生和发育中的作用; 2）探索Zfp 608缺陷对胎儿/出生后发育和适应性免疫应答的影响。T和B淋巴细胞的抗原受体基因组装是获得性免疫的一个基本方面，免疫球蛋白和T细胞几乎识别唯一参与的1和B淋巴细胞。Rag 1在淋巴细胞发育或哺乳动物个体发育过程中的作用尚不完全清楚。“Zfp 60 S过度表达Rag不足”），Rag 1胸腺细胞成熟，外周细胞稳态。1 S基因，Zfp 60 S。Zfp 60 S高度新生儿出生后熄灭。ZORI小鼠终生维持胸腺细胞Zfp 60 S。正常胸腺细胞中的ZORI突变Zfp 60 S严重损害Rag表达，为ZORI胸腺细胞中Zfp 60 S可能在产前和出生后早期发育提供了基础。针对ZFP 60 S存在的问题提出研究建议。其次，我们假设靶向缺失Zfp 60 S可能导致Rag基因的去阻遏和T细胞亚群的过早扩增，这可能提供一个模型来理解为什么与其他器官系统的发育相比，免疫系统的发育在个体发育中延迟。本研究的具体目的是：1）研究Zfp 60 S在胸腺细胞个体发生和发育中的作用，探讨Zfp 60 S缺陷对胎儿和出生后发育的影响，以及Zfp 60 S缺陷对获得性免疫的影响。

项目成果

Genetic and epigenetic regulation of Tcrb gene assembly.

• DOI: 10.1007/82_2011_138
• 发表时间: 2012
• 期刊: Current topics in microbiology and immunology
• 作者: M. Sikes;E. Oltz