Control of Thymocyte Development and Rag Expression by Zfp608

T淋巴细胞和B淋巴细胞的抗原受体基因组装是适应性免疫的一个基本方面，需要产生多种免疫球蛋白和I细胞受体，它们几乎可以识别一个物种可能遇到的任何病原体。抗原受体基因通过V(D)J重组有序组装的过程是由ragi和rag2酶催化的，这两种酶在前体T淋巴细胞和B淋巴细胞中唯一表达。然而，控制Ragi和Rag2基因表达或个体发生的机制，我们开发了一个同源菌株（ZORI，“Zfp608过表达Rag不足”），其Ragi和Rag2表达，胸腺细胞成熟和外周T细胞稳态存在缺陷。这一突变定位于18号染色体上含有一个已知基因Zfp608的位点。在野生型小鼠中，Zfp608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小鼠终生维持胸腺细胞表达Zfp608。ZORI突变产生胸腺细胞内在发育缺陷。Zfp608在正常胸腺细胞中的过表达严重损害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产后早期发育期间阻止Rag的表达。我们的研究结果提出了关于Zfp608调控机制和功能的几个问题，我们将在本研究计划中解决这些问题。首先，Zfp608在个体发育过程中是如何调控的，ZORI小鼠中Zfp608表达缺陷的原因是什么？其次，我们假设Zfp608的靶向缺失可能与免疫的发展有关：1)研究Zfp608在胸腺细胞发生和发育中的作用；2)探索Zfp608缺失对胎儿/出生后发育和适应性免疫反应的影响。抗原受体基因在T淋巴细胞和B淋巴细胞中的组装是适应性免疫的一个基本方面，而库免疫球蛋白和T淋巴细胞的识别几乎完全与B淋巴细胞有关。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”)与Rag1胸腺细胞成熟，外周细胞稳态。1S基因，Zfp60S。Zfp60S高新生儿出生后熄灭。ZORI小鼠终生维持胸腺细胞Zfp60S。正常胸腺细胞中ZORI突变Zfp60S严重损害Rag的表达，为ZORI胸腺细胞中Zfp60S可能在产前和产后早期发育中起作用提供了基础。Zfp60S的问题将研究方案。其次，我们假设Zfp60S的靶向缺失可能导致Rag基因的去抑制和T细胞亚群的过早扩增，这可能为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被延迟提供了一个模型。我们的具体目的是：1)研究Zfp60S在胸腺细胞发生和发育中的作用，探讨Zfp60S缺乏对胎儿/出生后发育和适应性免疫的影响

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