Abstract
Notch signaling regulates many fundamental events including lateral inhibition and boundary formation to generate very reproducible patterns in developing tissues. Its targets include genes of the bHLH hairy and Enhancer of split [E(spl)] family, which contribute to many of these developmental decisions. One member of this family in Drosophila, deadpan (dpn), was originally found to have functions independent of Notch in promoting neural development. Employing genome-wide chromatin-immunoprecipitation we have identified several Notch responsive enhancers in dpn, demonstrating its direct regulation by Notch in a range of contexts including the Drosophila wing and eye. dpn expression largely overlaps that of several E(spl) genes and the combined knock-down leads to more severe phenotypes than either alone. In addition, Dpn contributes to the establishment of Cut expression at the wing dorsal-ventral (D/V) boundary; in its absence Cut expression is delayed. Furthermore, over-expression of Dpn inhibits expression from E(spl) gene enhancers, but not vice versa, suggesting that dpn contributes to a feed-back mechanism that limits E(spl) gene expression following Notch activation. Thus the combined actions of dpn and E(spl) appear to provide a mechanism that confers an initial rapid output from Notch activity which becomes self-limited via feedback between the targets.
Highlights
Notch signaling is a well-conserved pathway across metazoans involved in the regulation of many fundamental events including lateral inhibition and boundary formation
More recently it has emerged that there is direct input of Notch into a neuroblast enhancer, the relevance of this regulation remains unclear [5]. dpn expression is detected in a wide range of other tissues including the wing, eye and leg imaginal discs, where it overlaps with well-characterised Notch target genes ([7,11,12] and Fig. 1)
Whether or not Dpn is directly regulated by Notch in these tissues has remained unclear, as the characterized neuroblast enhancer does not direct expression in the imaginal discs
Summary
Notch signaling is a well-conserved pathway across metazoans involved in the regulation of many fundamental events including lateral inhibition and boundary formation. The downstream targets involved in implementing these actions include genes of the bHLH Hairy and Enhancer of split (HES) gene family, which in Drosophila are located within the 60 kb E(spl) complex. Activity of the known targets cannot account for all of the functions of Notch, prompting us to perform genome wide chromatin immunoprecipitation (ChIP with anti-Su(H) antibody) to identify other Notch regulated genes [3,4]. One gene which emerged from these analyses was deadpan (dpn), itself a member of the Hairy/Enhancer of Split (HES) subclass of repressor basic Helix-Loop-Helix (bHLH) proteins, but one that had been primarily linked to the specification of neural cells. More recently it has become evident that dpn is Notch regulated in some contexts the extent to which it is a direct target and its relevance to Notch functions have remained enigmatic [5]
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