Inverse Regulation of Target Genes at the Brink of the Dpp Morphogen Activity Gradient. Offer Gerlitz¹, Oren Ziv¹, Rutie Finkelstein¹, Yaron Suissa¹, Tama Dinur¹, Girish Deshpande². 1) Developmental Biology and Cancer Research, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem, Israel; 2) Department of Molecular Biology, Princeton University, Princeton, NJ 08540.

   Dpp-dependent patterning in the wing imaginal disc of Drosophila melanogaster serves as a paradigm to understand how morphogen gradients specify various cell fates in a concentration-dependent manner. According to the current model, profile of the transcriptional response to the graded activity of Dpp, relies upon two opposing gradients of pMad and Brinker (Brk). However, this patterning model is inadequate to explain the expression of target genes, like vestigial and spalt, in lateral regions of the wing disc, where Dpp signal decline and Brk levels peak. We show that in contrast to the reciprocal repressor gradient mechanism, where Brk represses Dpp targets in medial regions, in lateral regions target expression is downregulated by Dpp signaling and activated by Brk. How is this inverse regulation achieved? By studying spalt expression in the different regions of the wing disc, we uncovered a novel circuitry where Brk induces expression of spalt at the periphery of the wing disc indirectly through repression of a negative regulator (NRS). On one hand, NRS represses spalt expression by binding to a cis-regulatory element that does not contain Brk binding sites. On the other, NRS is itself negatively regulated by Brk. Our findings constitute an important first step towards unraveling the workings of a morphogen gradient at the edges.