The basic Helix-Loop-Helix (bHLH) proteins represent a well-known class of transcriptional regulators. Many bHLH proteins act as heterodimers with members of a class of ubiquitous partners, the E-proteins. A widely-expressed class of inhibitory heterodimer partners- the Inhibitor of DNA-binding (ID) proteins- also exists. Genetic and molecular analyses in humans and in knockout mice implicate E-proteins and ID-proteins in a wide variety of diseases, belying the notion that they are non-specific partner proteins. Here, we explore relationships of E-proteins and ID-proteins to a variety of disease processes and highlight gaps in knowledge of disease mechanisms.

The E-proteins and Id-proteins are, respectively, the positive and negative heterodimer partners for the basic-helix-loop-helix protein family, and as such contribute to a remarkably large number of cell fate decisions. E-proteins and Id-proteins also function to inhibit or promote cell proliferation and cancer. Using a genetic modifier screen in Drosophila, we show that the Id-protein Extramacrochaetae enables growth by suppressing activation of the Salvador-Warts-Hippo pathway of tumor suppressors, activation that requires transcriptional activation of the expanded gene by the E-protein Daughterless. Daughterless protein binds to an intronic enhancer in the expanded gene, both activating the SWH pathway independently of the transmembrane protein Crumbs, and bypassing the negative feedback regulation that targets the same expanded enhancer. Thus the Salvador-Warts-Hippo pathway has a cell-autonomous function to prevent inappropriate differentiation due to transcription factor imbalance, and monitors the intrinsic developmental status of progenitor cells, distinct from any responses to cell-cell interactions.

In eye development the tasks of tissue specification and cell proliferation are regulated, in part, by the Pax6 and Pax6(5a) proteins respectively. In vertebrates, Pax6(5a) is generated as an alternately spliced isoform of Pax6. This stands in contrast to the fruit fly, Drosophila melanogaster, which has two Pax6(5a) homologs that are encoded by the eyegone and twin of eyegone genes. In this report we set out to determine the respective contributions that each gene makes to the development of the fly retina. Here we demonstrate that both eyg and toe encode transcriptional repressors, are expressed in identical patterns but at significantly different levels. We further show, through a molecular dissection of both proteins, that Eyg makes differential use of several domains when compared to Toe and that the number of repressor domains also differs between the two Pax6(5a) homologs. We predict that these results will have implications for elucidating the functional differences between closely related members of other Pax subclasses.

The Drosophila head vertex is composed of three ocelli, stereotypic bristle patterns and characteristic cuticles. It is derived from the fusion of two eye-antenna discs. The head vertex primordium is located at the anterior-dorsal region of the eye disc. The orthodenticle (otd) homeobox gene is expressed in the primordium and is functionally required for its development and patterning. Here we show that the Pax gene eye gone (eyg) is expressed adjacent to the otd expression domain in the eye disc. otd is required and sufficient to repress eyg transcription, thereby preventing eyg from expressing in the head vertex primordium. In otd mutant, eyg expression is derepressed in the head vertex primordium and is a major negative effector to block head vertex development. Therefore, otd not only needs to induce downstream effector genes to execute the development and patterning of the head vertex development, but also needs to actively repress the negative regulator eyg. In addition, eyg is required for the development of the lateral bristles in the head vertex. So eyg plays both positive and negative roles in head vertex development.