Tissue-specific enhancer repression through molecular integration of cell signaling inputs

Autor: Mojica-Vazquez, Luis Humberto, Benetah, Mikhail H., Baanannou, Aissette, Bernat-Fabre, Sandra, Deplancke, Bart, Cribbs, David L., Bourbon, Henri-Marc, Boube, Muriel
Rok vydání: 2016
Předmět:
lcsh:QH426-470
Bioinformatics
Gene Expression
Immunostaining
Research and Analysis Methods
Biochemistry
Database and Informatics Methods
Protein Domains
Cell Signaling
Sequence Motif Analysis
Endopeptidases
DNA-binding proteins
Morphogenesis
Medicine and Health Sciences
Genetics
Animals
Drosophila Proteins
Homeobox
Gene Regulation
Receptors
Invertebrate Peptide
Molecular Biology Techniques
Molecular Biology
Musculoskeletal System
Homeodomain Proteins
Staining
Binding Sites
Limbs (Anatomy)
Biology and Life Sciences
Proteins
Extremities
Cell Biology
Regulatory Proteins
ErbB Receptors
Repressor Proteins
lcsh:Genetics
Drosophila melanogaster
Enhancer Elements
Genetic
Organ Specificity
Specimen Preparation and Treatment
Legs
Anatomy
Sequence Analysis
Protein Binding
Signal Transduction
Transcription Factors
Research Article
Cloning
Zdroj: PLoS Genetics
PLoS Genetics, Vol 13, Iss 4, p e1006718 (2017)
ISSN: 1553-7404
Popis: 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.
Author summary Limb morphogenesis is controlled by a well-known genetic cascade, mobilizing both cell signaling and tissue-specific transcription factors (TFs). However, how their concerted action refines gene expression remains to be deciphered. It is thus crucial to understand how cell signaling inputs are integrated by transcriptional “enhancers”. The Drosophila leg provides a good paradigm to dissect the molecular mechanisms underlying gene regulation. Here, we used the bric-a-brac2 (bab2) gene as a model to study the integrated regulation of patterning genes implicated in tarsal segmentation. bab2 expression in the leg primordium is dynamic and complex, going from initial broad distal expression to precisely positioned tarsal rings. By genetic and molecular analyses, we show here that the cell signaling-responding TFs C15 and Bowl interact directly with the limb-specific bab2 enhancer as a repressive duo. Moreover, C15 acts independently of its partner Aristaless through physical interaction with the Dll activator. We propose that Dll induces early circular bab2 expression pattern, then EGFR signaling-induced C15 in the distalmost cells competes with Dll for LAE binding and resolves bab2 pattern as a ring. Taken together our data shed light on how the concerted action of a quartet of transcription factors reshapes gene expression during limb proximo-distal axis development.
Databáze: OpenAIRE
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