Control of Thymocyte Development and Rag Expression by Zfp608

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，需要产生一系列免疫球蛋白和I细胞受体，它们几乎识别一个物种可能遇到的任何病原体。V(D)J重组参与抗原受体基因有序组装的过程是由RAG-I和RAG-2酶催化的，这两个酶在前体T和B淋巴细胞中唯一表达。然而，控制RagI和Rag2基因表达或个体发育的机制我们培育了一株同源菌株(Zori，“Zfp608过度表达Rag1和Rag2不足”)，该菌株在RagI和Rag2基因表达、胸腺细胞成熟和外周T细胞动态平衡方面存在缺陷。这种突变映射到18号染色体上的一个基因座，该基因座包含一个已知基因Zfp608。在野生型小鼠中，Zfp608基因在新生胸腺中高度表达，但在出生后就消失了。相比之下，Zori小鼠终生维持胸腺细胞Zfp608的表达。Zori突变会产生胸腺细胞固有的发育缺陷。Zfp608在正常胸腺细胞中的过度表达严重损害了RAG的表达，为Zori胸腺细胞发育缺陷提供了潜在的机制。因此，Zfp608的正常功能可能是在产前和出生后早期发育过程中阻止RAG的表达。我们的结果提出了几个关于Zfp608调控机制和功能的问题，我们将在本研究提案中解决这些问题。首先，Zfp608在个体发育过程中是如何调节的，Zfp608在Zori小鼠中表达缺陷的原因是什么？第二，我们假设Zfp608基因的靶向缺失可能对免疫系统的发育有一定的影响，目的是：1)研究Zfp608基因在胸腺细胞个体发育中的作用；2)探讨Zfp608基因缺失对胎儿/出生后发育和获得性免疫反应的影响。项目概述T和B淋巴细胞抗原受体基因的组装是获得性免疫的一个基本方面，免疫球蛋白和T几乎唯一地识别所涉及的1和B淋巴细胞。Rag1在淋巴细胞发育或哺乳动物个体发育中的作用尚不完全清楚。“Zfp60S过表达RAg不足”)，Rag1胸腺细胞成熟，外周细胞动态平衡。1S基因，Zfp60S。Zfp60S高度新生儿出生后熄灭。Zori小鼠终生维持胸腺细胞Zfp60S。Zori突变Zfp60S在正常胸腺细胞中严重损害RAG的表达，为Zori胸腺细胞Zfp60S在产前和出生后早期发育中的作用提供了基础。Zfp60S的问题将研究建议。Zfp60S调控Zfp60S第二，我们假设靶向缺失Zfp60S可能导致RAG基因的下调和T细胞亚群的过早扩张，这可能为理解为什么免疫系统在个体发育中的发育比其他器官系统的发育迟缓提供了一个模型。我们的具体目标是：1)研究Zfp60S在胸腺细胞个体发育中的作用，探讨Zfp60S缺乏对胎儿/出生后发育和获得性免疫的影响

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