FUNCTIONS OF THE NURR 1 SUBFAMILY OF NUCLEAR RECEPTORS

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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.