Launching the molecular genetic investigation of the ecdysone signaling cascade: a tribute to David S. Hogness (1925-2019).

The steroid hormone 20-OH-ecdysone ("ecdysone") regulates viability, metamorphosis, and fertility in insects. Fifty years ago, little was known about the molecular basis of ecdysone action except for cytological evidence that a regulatory hierarchy of gene expression is involved. To address this challenge, David Hogness' lab developed methods for differential cDNA hybridization using a novel macroarray strategy that foreshadowed microarray technology. In the late 1970s, they isolated ecdysone-regulated genes from Drosophila melanogaster salivary glands during the larval-to-pupal transition at the onset of metamorphosis. To mark the centenary of Hogness' birth, we report on this foundational work and fill a historical gap by providing as online Supplementary materials the unpublished manuscript presenting the methodology and results. The isolated cDNA clones included larval Intermolt genes that are rapidly repressed by ecdysone (such as Sgs glue-protein genes) and Late-response genes induced indirectly by ecdysone, notably the Eig71E Late-gene cluster. Recent data by others provide compelling evidence that both sets of encoded proteins serve protective roles during metamorphosis, reducing the risk of predation and infection. Early genes that are rapidly and directly activated by ecdysone were cloned in the 1980s by chromosomal walking in Hogness' and other labs. These encode highly conserved transcription factors that control multiple levels of the ecdysone response. Thus, the original cloning of Intermolt and Late ecdysone-regulated genes illuminated a molecular pathway in which a systemic hormonal signal controls a set of transcription factors that orchestrate expression of "worker proteins" that enhance organismal survival during development.