Non-Mammalian Nuclear Receptors: From Evolution to Human Disease.

In 1964, Ulrich Clever published a landmark paper on the actions of 20-hydroxyecdysone (20E), the hormone that regulates molting and metamorphosis in insects. Based on the puffing activity of Chironomus tentans salivary gland polytene chromosomes, Clever was able to establish a pattern of gene activation in response to 20E A decade later, Michael Ashburner, utiliz-ing Drosophila melanogaster salivary gland polytene chromosomes, established a formalized model (the “Ashburner Model”) where 20E, bound to its receptor, activates a set of primary (“early”) target genes. The products of these genes, in turn, repress their own expression, and activate the transcription of secondary (“late”) target genes that control metamorphosis [2]. Subsequently, it was shown that the receptor for 20E, EcR, was an insect member of the nuclear receptor superfamily, and EcR, along with its heterodimer partner Usp (homolog of RXR), bind 20E and activate a set of early target genes at the onset of metamorphosis 4]. Additionally, many of the early gene products were also nuclear receptors that regulated the transcription of the secondary late genes Thus, the fruit fly as an invertebrate model system for studying nuclear receptor signaling was established. The regulation of metamorphosis, in association with powerful fruit fly genetics, became an important system for deciphering the mechanisms of nuclear receptor action, and subsequent studies demonstrated the utility that