FUNCTIONS OF THE NURR 1 SUBFAMILY OF NUCLEAR RECEPTORS

核受体超家族组成最大的家族 到目前为止已发现并控制多种真核转录因子 包括发育、生理和行为过程。这个 超家族包括类固醇、维生素和许多 功能尚未确定的“孤儿”受体。这个 NOR1孤儿受体亚家族由三个密切相关的家族组成 与之相互作用的基因产物(Nurr1、Nur77和NOR-1) 增强子DNA序列及其构象活性 转录因子，不需要配基结合。他们 是直接早期基因的产物，这些基因表现出明显的 构成成分表达的重叠时空模式 和可诱导水平，指示它们可能具有共享的和 不同的转录调控功能。我们的总体目标是 研究是建立集体的、有选择的发展和 受Nurr1亚家族调控的生理功能 转录因子。我们在这方面的当务之急是 建议是确立托儿所1的职能。首先，我们将完成 我们对Nurr1之间功能冗余的可能性的分析 通过检查时空表达谱来确定子家族成员 NOR-1。第二，我们将确定共表达的靶基因 与Nurr1及其亚家族成员一起并由其管理。我们有 证实了Nurr1亚家族可以参与神经内分泌 调节下丘脑/垂体/肾上腺轴，并提供 有证据表明，Nurr1可能选择性地调节这一轴的发育。 我们将确定我们确定的神经内分泌靶标是否 在发育过程中由Nurr1选择性地调节。第三，我们将 使用空突变小鼠建立Nurr1消融的后果 我们生成的模型。最后，我们将产生缺乏的小鼠 NOR-1以建立其选择性的体内功能以及 亚科的集体功能。我们提出的实验 将为我们提供关于这个角色的有价值的新见解 调控哺乳动物的转录因子亚家族 发育和生理动态平衡。

The nuclear receptor superfamily comprises the largest family of eukaryotic transcription factors identified to date and controls a variety of developmental, physiological and behavioral processes. The superfamily includes receptors for steroids, vitamins and numerous "orphan" receptors whose functions have not been established. The Nurr 1 subfamily of orphan receptors consists of three closely related gene products (nurr1, nur77 and NOR-1) that interact with the same enhancer DNA sequences and function as constitutively active transcription factors without a requirement for ligand binding. They are products of immediate early genes that display distinct but overlapping spatiotemporal patterns of expression at the constitutive and inducible level indicating that they may have both shared and distinct transcription regulatory functions. The overall goal of our research is to establish the collective and selective developmental and physiological functions that re regulated by the nurr1 subfamily of transcription factors. Our immediate priority within the context of this proposal is to establish the functions of nurr1. First, we will complete our analysis of the potential for functional redundancy among nurr1 subfamily members by examining the spatiotemporal expression profile of NOR-1. Second, we will identify target genes that are coexpressed with and regulated by nurr1 and its subfamily members. We have established that the nurr1 subfamily can participate in neuroendocrine regulation of the hypothalamic/pituitary/adrenal axis and that provide evidence that nurr1 may selectively regulate development of this axis. We will determine whether the neuroendorine targets we identified are selectively regulated by nurr1 during development. Third, we will establish the consequences of nurr1 ablation using a null mutant mouse model we have generated. finally, we will generate mice lacking NOR-1 to establish its selective in vivo functions as well as the collective functions of the subfamily. The experiments we propose will provide us with valuable new insights into the role of this subfamily of transcription factors in regulating mammalian development and physiological homeostasis.