ANALYSIS OF A MURINE HOMEOBOX LOCUS

小鼠Hox基因系统的鉴定，这在小鼠Hox基因系统中起着至关重要的作用。 在建立身体计划的作用，是由范式预测 某些关键发展进程的基本保护， 后生动物。这一范例得到了研究的证实，研究表明， 鼠Hox基因系统与果蝇的同源异型基因系统相似， HOM-C，结构，成簇组织，前后表达 模式，大概在其分配位置的功能， 身份因此，该项目的长期目标是：（一） 确定鼠Hoxc基因座在多大程度上符合这一前提， (ii)了解一些转录控制机制， 促进Hox基因独特的时空限制模式 表情以下具体目标确定了实现以下目标的战略： 这些目标： (1)Hoxc-10基因的假定形态发生控制功能将在 通过使用异源的转基因小鼠中的靶向错误表达分析 特定区域的控制要素。基于独特的空间限制 Hoxc-10在小鼠发育过程中的表达模式， 功能域仅限于后体区域，包括 发育后肢、骨盆带和泌尿生殖系统。因此，委员会认为， 这些研究有望阐明假定的 Hoxc-10特有的发育控制功能，有助于我们 对Hox基因功能的一般了解。 (2)正确的发育需要精确协调的Hox基因表达 模式.这些模式可能是由复杂的顺式作用介导的， 监管要素。分离的调节元件所需的 Hoxc-9和Hoxc-10的正确表达将通过缺失进行 转基因小鼠中相关Hoxc/lacZ报告基因构建体的分析 小鼠这将是所有重要的第一步，在分析 控制Hoxc-9和-10转录的分子机制，因此 有助于我们理解建立区域 基因表达的特异性是发展的关键问题。 (3)有一种假说认为， Hox和HOM-C的前后顺序表达模式 基因表明高度保守的转录控制机制 指定位置标识，将通过检查功能 HOM-C位置控制元件和HOM-C响应元件的保存 元件在利用LacZ报告基因构建体的转基因小鼠中的表达。这些 实验的目的是确定最小的元素， 在建立区域特异性基因表达沿着 前后胚轴 该项目有望有助于了解分子 某些先天性畸形的潜在机制以及 致畸物质在人类发育过程中的作用。后 假设Hox基因指定细胞身份，这些研究也可能 影响了我们对疾病的理解， 在癌症中的典型特征。

The identification of the murine Hox gene system, which plays a crucial role in establishing the body plan, was guided by the paradigm predicting essential conservation of certain key processes of development among most metazoans. This paradigm was substantiated by studies indicating that the murine Hox gene system parallels the homeotic gene system of Drosophila, HOM-C, in structure, clustered organization, antero-posterior expression patterns, and presumably in its function of assigning positional identities. Accordingly, this project's long term objectives are: (i) establishing to which extent the murine Hoxc locus fits this premise and (ii) understanding some of the transcriptional control mechanisms that facilitate the distinct spatio-temporally restricted patterns of Hox gene expression. The following specific aims define a strategy for achieving these goals: (1) Putative morphogenetic control functions of the Hoxc-10 gene will be analyzed by targeted misexpression in transgenic mice using heterologous region-specific control elements. Based on the unique spatially restricted expression pattern of Hoxc-10 during mouse development, its presumptive domain of function is restricted to posterior body regions including the developing hindlimb, pelvic girdle and urogenital system. Accordingly, these studies promise to elucidate essential aspects of putative developmental control functions specific for Hoxc-10 and contribute to our general understanding of Hox gene function. (2) Proper development requires precisely orchestrated Hox gene expression patterns. These patterns are presumably mediated by complex cis-acting regulatory elements. The isolation of regulatory elements required for the correct expression of Hoxc-9 and -10 will be performed by deletion analyses of pertinent Hoxc/lacZ reporter gene constructs in transgenic mice. This will represent all important first step in the analysis of the molecular mechanisms controlling transcription of Hoxc-9 and -10, thus contributing to our understanding of the establishment of regional specificities of gene expression, a key problem of development. (3) The hypothesis that the remarkable similarities in the distinct, serially arranged antero-posterior expression patterns of Hox and HOM-C genes indicate highly conserved transcriptional control mechanisms for specifying positional identities, will be tested by examining functional conservation of HOM-C positional control elements and HOM-C responsive elements in transgenic mice utilizing LacZ reporter gene constructs. These experiments are aimed at identifying minimal elements that function universally in establishing region-specific gene expression along the antero-posterior embryonic axis. This project promises to contribute to an understanding of the molecular mechanisms underlying certain congenital malformations and the molecular actions of teratogenic substances during human development. Following the premise that Hox genes specify cellular identities, these studies may also have an impact on our understanding of diseases involving a loss of such identities as typified in cancer.