Analyzing nuclear receptor activation and repression: The role of ultraspiracle, the Drosophila RXR, in Drosophila eye development

Nuclear hormones regulate many aspects of animal development and are mediated by nuclear receptors, a large family of transcription factors. Many nuclear receptors are highly conserved including Ultraspiracle (USP), the Drosophila homologue of the Retinoid X Receptor. A heterodimer of USP and another nuclear receptor, the Ecdysone Receptor (EcR) mediates the molting hormone ecdysone, which is necessary for adult tissue morphogenesis.; Many aspects of Drosophila development are regulated by usp. Loss of usp results in faster morphogenetic furrow movement, premature differentiation and disarranged ommatidial clusters in the developing Drosophila eye. Two pathways regulating these processes, the hedgehog/decapentaplegic and the hairy/extramacrochaete pathways, appear independent of each other and of usp. In general, usp affects the timing of cellular differentiation. Premature differentiation results in a decrease in cycling cells posterior to the furrow. Additionally, loss of usp results in misexpressed scabrous, a gene involved in the Notch pathway. Exogenous USP in usp clones mapsusp regulation of furrow movement, neuronal differentiation and ommatidial organization to the posterior half of the furrow. usp continues to function posterior to the furrow. In wing development, usp appears to perform similar roles.; Three different usp alleles exist. usp 3 and usp4 are point mutations in the DNA-binding domain (DBD) and produce mutant proteins capable of heterodimerization but incapable of DNA-binding. usp2 is a protein null. usp3 and usp 4 are incapable of repressing certain ecdysone response genes, but can activate other targets, suggesting that the DBD is not essential for the regulation of these genes. Despite this result, neither usp 3 nor usp4 are wild type for activation of all ecdysone responsive genes.; Ecdysone is necessary for morphogenetic furrow movement, but USP, part of the ecdysone receptor, represses this process. USP could be activating and repressing the same set of furrow genes in the eye depending on the presence or absence of ligand. Supporting this model, USP both activates and represses the ecdysone-responsive BrC-Z1, which is involved in furrow movement. However, neither the Ecdysone Receptor nor a corepressor appears to play a role in eye development.