MURINE HOMEOBOX LOCUS

小鼠HOX基因系统的鉴定，它起着至关重要的作用 在建立身体计划中的作用，是由范式预测指导的 在社会变革管理计划中对某些关键发展进程进行必要的保护 后生动物。这一范式得到了研究的证实，研究表明 小鼠HOX基因系统与果蝇的同源同源基因系统相似， HOM-C，在结构上，集群组织，前后表达 模式，可能是在其分配位置的功能中 身份。因此，该项目的长期目标是：(I) 建立小鼠Hoxc基因座在多大程度上符合这一前提 (Ii)了解一些转录调控机制， 促进HOX基因不同的时空限制性模式 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基因可能的形态发生调控功能 利用异源基因在转基因小鼠中的靶向性错误表达分析 区域特定的控制元素。基于唯一的空间受限的 Hoxc-10在小鼠发育过程中的表达模式及其推测 功能域仅限于身体后部区域，包括 后肢、骨盆带和泌尿生殖系统发育。因此， 这些研究承诺阐明假设的基本方面。 Hoxc-10特有的发育控制功能，并有助于我们的 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调节的。 监管要素。隔离监管要素所需的 Hoxc-9和-10的正确表达将通过删除来实现 转基因中相关的HOXC/LacZ报告基因构建分析 老鼠。这将是分析的所有重要的第一步 控制Hoxc-9和-10转录的分子机制，因此 有助于我们理解区域组织的建立 基因表达的特殊性，这是发展的一个关键问题。 (3)假设在不同的， HOX和Hom-C的前后顺序表达模式 基因表明高度保守的转录调控机制 指定位置身份，将通过检查功能进行测试 Hom-C位置控制元件的保守性和Hom-C响应 利用LacZ报告基因构建的转基因小鼠中的元素。这些 实验的目的是确定起作用的最小元素 在建立区域特异性基因表达方面具有普遍意义 前后胚轴。 这个项目承诺将有助于理解分子。 某些先天畸形的发病机制及其分子机制 致畸物质在人类发育过程中的作用。紧随其后的是 假设HOX基因规定了细胞身份，这些研究还可能 会影响我们对疾病的理解，这些疾病涉及到 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.