Abstract
Drosophila leg morphogenesis occurs under the control of a relatively well-known genetic cascade, which mobilizes both cell signaling pathways and tissue-specific transcription factors. However, their cross-regulatory interactions, deployed to refine leg patterning, remain poorly characterized at the gene expression level. Within the genetically interacting landscape that governs limb development, the bric-à-brac2 (bab2) gene is required for distal leg segmentation. We have previously shown that the Distal-less (Dll) homeodomain and Rotund (Rn) zinc-finger activating transcription factors control limb-specific bab2 expression by binding directly a single critical leg/antennal enhancer (LAE) within the bric-à-brac locus. By genetic and molecular analyses, we show here that the EGFR-responsive C15 homeodomain and the Notch-regulated Bowl zinc-finger transcription factors also interact directly with the LAE enhancer as a repressive duo. The appendage patterning gene bab2 is the first identified direct target of the Bowl repressor, an Odd-skipped/Osr family member. Moreover, we show that C15 acts on LAE activity independently of its regular partner, the Aristaless homeoprotein. Instead, we find that C15 interacts physically with the Dll activator through contacts between their homeodomain and binds competitively with Dll to adjacent cognate sites on LAE, adding potential new layers of regulation by C15. Lastly, we show that C15 and Bowl activities regulate also rn expression. Our findings shed light on how the concerted action of two transcriptional repressors, in response to cell signaling inputs, shapes and refines gene expression along the limb proximo-distal axis in a timely manner.
Highlights
In developing arthropod and vertebrate appendages, morphogen gradients play critical roles in instructing the spatially-restricted expression of patterning genes that mostly encode transcription factors (TFs) [1, 2]
Limb morphogenesis is controlled by a well-known genetic cascade, mobilizing both cell signaling and tissue-specific transcription factors (TFs)
We propose that Dll induces early circular bab2 expression pattern, epidermal growth factor receptor (EGFR) signaling-induced C15 in the distalmost cells competes with Dll for leg/antennal enhancer (LAE) binding and resolves bab2 pattern as a ring
Summary
In developing arthropod and vertebrate appendages, morphogen gradients play critical roles in instructing the spatially-restricted expression of patterning genes that mostly encode transcription factors (TFs) [1, 2]. How their expression domains are set up precisely and how their cross-regulation refines pattern layouts, remain to be deciphered, by characterizing the cis-regulatory modules within the gene regulatory networks governing limb development. During the first and second instar larval stages, in response to antagonistic wingless (wg) and decapentaplegic (dpp) cell signaling pathways, the TF-encoding Distal-less (Dll), dachshund (dac) and homothorax (hth) genes are activated in broad concentric domains within the leg disc, that prefigure the distal, medial and proximal subdivisions of the adult appendage, respectively [3]. By the end of the third instar larval (L3) stage, the leg disc is highly folded presaging movements towards a tri-dimensional structure
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