DEVELOPMENTAL GENETICS OF THYMUS ORGANOGENESIS

这项研究的长期目标是了解遗传和 胸腺器官发生和功能的分子机制。 影响胎儿胸腺发育的人类出生缺陷可能两者都有 遗传原因，如DiGeorge综合征和瓣心面综合征 (发生在1/5000活产婴儿中)和环境来源。最早的 胎儿胸腺发育的几个步骤涉及上皮间充质 咽内胚层来源的上皮细胞与细胞间的相互作用 神经脊来源的间充质细胞。通过对突变小鼠的分析 菌株和基因表达的研究，一些候选基因已经被 在鼠标中识别的可能参与这些早期步骤的基因。 然而，这些基因之间的关系及其在 人们对这一过程知之甚少。Hoxa3和Pax1基因是 转录因子已被证明在调节 胸腺发育。Hoxa3在两种内胚层上皮细胞中均有表达 和有助于胸腺发育的神经脊间充质，而 Pax1仅在内胚层上皮细胞表达。突变的小鼠 因为Hoxa3不形成胸腺Pax1突变小鼠具有发育不良的胸腺， 在T细胞选择的早期步骤中存在缺陷。使用基因 分析表明，这两个基因协同作用影响 胸腺发育与胸腺细胞选择。据我们所知，这一结果 首次证明了Hox和Pax之间的遗传相互作用 老鼠身上的基因。此外，Pax1的表达被特别下调 在Hoxa3突变体中。我们将在小鼠身上使用遗传和分子方法来 测试Hoxa3和Pax`在 指导早期胸腺器官发生的内胚层。的具体目标 建议的研究是：1)在它们的任一个中特异性地表达Hoxa3 内胚层或神经脊，确定Hoxa3的组织特异性 在胸腺发育中的作用，以及Hoxa3是否调节Pax1 2)探讨小鼠胸腺发育不良的起源。 Hoxa3.Pax1复合突变体，并确定潜在的下游靶点 Hoxa3和Pax1在早期胸腺器官发生中的作用；3)检测 外源添加的候选生长因子以绕过阻止 这些突变体中的胸腺器官发生和功能。建议进行的研究 试图定义一条调节这一点的遗传途径，人们对此知之甚少 发展过程。

The long term goal of this research is to understand the genetic and molecular mechanisms underlying organogenesis and function of the thymus. Human birth defects that affect fetal thymus development can have both genetic causes, as in DiGeorge Syndrome and velocardiofacial syndrome (occurring in 1/5000 live births), and environmental origins. The early steps of fetal thymus development involve epithelial-mesenchymal interactions between pharyngeal endoderm derived epithelial cells and neural crest derived mesenchymal cells. Through analysis of mutant mouse strains and gene expression studies, a number of candidate genes have been identified in the mouse that may be involved in these early steps. However, the relationships between these genes and their specific roles in this process are poorly understood. The Hoxa3 and Pax1 genes are transcription factors that have been shown to have a role in regulating thymus development. Hoxa3 is expressed in both the endodermal epithelium and neural crest mesenchyme that contribute to thymus development, while Pax1 is expressed only in the endodermal epithelium. Mice which are mutant for Hoxa3 do not form a thymus Pax1 mutant mice have a hypoplastic thymus, and are deficient in early steps in T cell selection. Using a genetic analysis, we have shown that these two genes act synergistically to affect thymus development and thymocyte selection. To our knowledge, this result is the first demonstration of a genetic interaction between Hox and Pax genes in mice. In addition, Pax1 expression is specifically down-regulated in Hoxa3 mutants. We will use genetic and molecular approaches in mice to test the hypothesis that Hoxa3 and Pax` are interacting specifically in the endoderm to direct early thymus organogenesis. The specific aims of the proposed research are: 1) to express Hoxa3 specifically in either them endoderm or neural crest, to determine the tissue specificity of Hoxa3 action in thymus development, and to address whether Hoxa3 regulates Pax1 expression; 2) to investigate the origin of the thymic hypoplasia in Hoxa3. Pax1 compound mutants, and identify potential downstream targets for Hoxa3 and Pax1 in early thymus organogenesis; and 3) test the ability of exogenously added candidate growth factors to bypass the block in thymus organogenesis and function in these mutants. The proposed studies seek to define a genetic pathway the regulates this poorly understood developmental process.