Sevenless: its function and structure in the specification of the <i>Drosophila</i> R7 photoreceptor

The fly eye is composed of hundreds of ommatidia, each containing a stereotyped pattern of photoreceptors and assorted support cells. Over the past 50 years, molecular genetic studies have illuminated how the fates of many of these cells are specified. As a result, the field has become a classic paradigm for cell-fate specification during animal development. The initial focus of the studies was the sevenless (sev) mutant, in which the cell normally destined to become the R7 photoreceptor instead develops into a lens-secreting support cell. This phenotype served as the entry point into the patterning mechanisms underlying ommatidial fate specification. sev was found to encode a receptor tyrosine kinase (RTK) expressed on the plasma membrane of the R7 precursor. Its ligand-Bride of Sevenless (Boss)-was then identified as a plasma membrane protein expressed on a neighboring cell, the presumptive R8 photoreceptor. Here, I present a personal perspective on the studies of Sev, from its discovery to the present day, beginning with the characterization of its loss-of-function phenotype and culminating in the highly detailed description of its biological role and the molecular mechanism by which it transduces the R8-to-R7 Boss signal. These studies have revealed surprisingly complex and novel properties of this seemingly simple signaling mechanism, including (i) the unexpected circuitry by which Sev signaling is integrated with that of the Drosophila EGF receptor and Notch to specify 3 distinct cell types (R7 and R1/6 photoreceptors and the lens-secreting cone cells) and (ii) the likely discovery of a new molecular mechanism of RTK activation in which transendocytosis of Boss from the presumptive R8 into the R7 precursor directs Sev to a select endocytic compartment, where it is activated by a conformation state induced by low pH. Further, I address evolutionary studies of Sev and Boss, which indicate that their roles as ligand and receptor are restricted to flies, and pose the intriguing question of whether R7 photoreceptors outside Diptera are specified by similar signaling logic but different molecular machinery.