DEVELOPMENTAL GENETICS OF THYMUS ORGANOGENESIS

这项研究的长期目标是了解遗传和 器官发生和胸腺功能的分子机制。 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velocardiofacial综合征 （发生率为1/5000活产）和环境起源。早期 胎儿胸腺发育的步骤涉及上皮-间充质 咽内胚层来源的上皮细胞与 神经嵴来源的间充质细胞。通过分析突变小鼠 菌株和基因表达的研究，一些候选基因已被 在小鼠中发现了可能参与这些早期步骤的基因。 然而，这些基因之间的关系和它们在 人们对这一过程知之甚少。Hoxa 3和Pax 1基因是 转录因子，已被证明有调节作用， 胸腺发育Hoxa 3表达于内胚层上皮和 和神经嵴间充质，有助于胸腺发育，而 Pax 1仅在内胚上皮中表达。突变小鼠 对于Hoxa 3不形成胸腺的Pax 1突变小鼠具有发育不全的胸腺， 并且在T细胞选择的早期步骤中有缺陷。使用遗传 分析，我们已经表明，这两个基因协同作用，影响 胸腺发育和胸腺细胞选择。据我们所知，这一结果 首次证明了Hox和Pax之间的基因互动 老鼠的基因此外，Pax 1表达特异性下调， 在Hoxa 3突变体中。我们将在小鼠中使用遗传和分子方法， 测试Hoxa 3和Pax“在特定的环境中相互作用”的假设。 指导早期胸腺器官发生的内胚层。的具体目标 本研究的主要目的是：1）在这两种基因中特异性表达Hoxa 3 内胚层或神经嵴，以确定Hoxa 3的组织特异性 胸腺发育中的作用，并解决Hoxa 3是否调节Pax 1 表达; 2）探讨胸腺发育不全的起源， Hoxa 3. Pax 1复合突变体，并确定潜在的下游靶点 Hoxa 3和Pax 1在胸腺器官发生早期的表达; 3）检测Hoxa 3和Pax 1在胸腺器官发生早期的表达能力。 外源性添加的候选生长因子， 胸腺器官发生和功能在这些突变体。拟议的研究 试图定义一个遗传途径，调节这个鲜为人知的 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.