HORMONAL CONTROL OF GENETIC HIERARCHIES IN DEVELOPMENT

拟议研究的长期目标是确定 类固醇激素控制组织的分子遗传学机制 发展。这是包括人类在内的高等动物的普遍问题， 对理解类固醇的作用尤为重要 荷尔蒙在癌症的发生中起到了作用。更具体地说，这是 研究的方向是对基因的分子定义 影响发展协调的监管等级制度 一组组织对类固醇激素作出反应的途径。果蝇 黑腹鱼是这些研究的首选生物体，因为它 包括高等动物中唯一一个定义明确的 类固醇激活的基因调控体系。这个层次结构是 诱导的多线染色体膨化程序 幼虫唾液腺由类固醇激素蜕皮激素的脉冲作用 幼虫寿命的结束--启动向成虫蜕变的脉冲 通过诱导一系列的发育途径的协调变化 目标组织。由Ashburner提出的用于产生这些的模型 转录泡芙由至少三个基因层次组成 排名。从编码蜕皮激素受体蛋白的基因开始， 转录六个“早期”调控基因，负责 第一组喷雾是由蜕皮激素受体复合体诱导的。蛋白质 由这些早期基因编码，然后诱导转录一个更大的 一组负责下一组喷雾的基因。克隆和 蜕皮激素受体基因(ECR)和两个早期基因的特征 本实验室的基因(E74、E75)的结果与 Ashburner模型，并表明遗传调控层次类似于 阿什伯纳提出的这一点也可能支配着 其他参与变态的靶组织。由此产生的“组织” 协调模型“提出了在这些相关问题中的第三位 组织特异性层次结构由“效应”基因组成 组织形态和功能特性的变化 构成了其发展道路的下一步。实验性的 计划针对该模型的测试和进一步开发。 在第一阶段，E74和E75的表达在细胞中的分布 靶组织，以及ECR基因在产生这些组织中所起的作用 分配，将被确定。随后，其他早期基因将被 克隆和类似的特征，然后克隆基因 在特定的靶组织中受早期基因蛋白和 测试这些基因的效应器特性。突变研究将 也可以用来确定这些基因之间的相互作用 层级结构。

The long-term objective of the proposed research is to determine the molecular genetic mechanisms by which steroid hormones control tissue development. This is a general problem in higher animals including humans, and is of particular importance to an understanding of the role steroid hormones play in the generation of cancers. More specifically, this research is directed toward the molecular definition of the genetic regulatory hierarchies that effect the coordination of the developmental pathways of a set of tissues in response to a steroid hormone. Drosophila melanogaster is the preferred organism for these studies because it includes the only example among higher animals of a well defined steroid-activated genetic regulatory hierarchy. This hierarchy is manifested by the program of polytene chromosome puffing induced in the larval salivary glands by a pulse of the steroid hormone ecdysone at the end of larval life - a pulse that initiates metamorphosis to the adult fly by inducing a coordinated change in the developmental pathways of a set of target tissues. The model proposed by Ashburner for the generation of these transcription puffs consists of a genetic hierarchy of at least three ranks. Starting with the gene encoding the ecdysone receptor protein, the transcription of a half-dozen "early" regulatory genes responsible for the first set of puffs is induced by the ecdysone-receptor complex. Proteins encoded by these early genes then induce the transcription of a much larger set of genes responsible for the next set of puffs. The cloning and characterization of the ecdysone receptor gene (EcR) and two of the early genes (E74, E75) in this laboratory have yielded results consistent with the Ashburner model and indicate that genetic regulatory hierarchies akin to that proposed by Ashburner may also govern the ecdysone response of the other target tissues involved in metamorphosis. The resulting "tissue coordination model" proposes that the third rank in these related tissue-specific hierarchies consists of "effector" genes which effect the change in the tissue's morphological and functional properties that constitute the next step in its developmental pathway. The experimental plan is directed toward the testing and further development of this model. In the first phase, the distribution of E74 and E75 expression among the target tissues, and the role played by the EcR gene in generating that distribution, will be determined. Subsequently, other early genes will be cloned and similarly characterized, followed by the cloning of genes regulated by the early gene proteins in particular target tissues and the testing of these genes for effector properties. Mutational studies will also be used to determine the interaction among the genes in these hierarchies.