Atrophin contributes to the negative regulation of epidermal growth factor receptor signaling in Drosophila.
Dentato-rubral and pallido-luysian atrophy (DRPLA) is a dominant, progressive neurodegenerative disease caused by the expansion of polyglutamine repeats within the human Atrophin-1 protein. Drosophila Atrophin and its human orthologue are thought to function as transcriptional co-repressors. Here, we report that Drosophila Atrophin participates in the negative regulation of Epidermal Growth Factor Receptor (EGFR) signaling both in the wing and the eye imaginal discs. In the wing pouch, Atrophin loss of function clones induces cell autonomous expression of the EGFR target gene Delta, and the formation of extra vein tissue, while overexpression of Atrophin inhibits EGFR-dependent vein formation. In the eye, Atrophin cooperates with other negative regulators of the EGFR signaling to prevent the differentiation of surplus photoreceptor cells and to repress Delta expression. Overexpression of Atrophin in the eye reduces the EGFR-dependent recruitment of cone cells. In both the eye and wing, epistasis tests show that Atrophin acts downstream or in parallel to the MAP kinase rolled to modulate EGFR signaling outputs. We show that Atrophin genetically cooperates with the nuclear repressor Yan to inhibit the EGFR signaling activity. Finally, we have found that expression of pathogenic or normal forms of human Atrophin-1 in the wing promotes wing vein differentiation and acts as dominant negative proteins inhibiting endogenous fly Atrophin activity.
Charroux
Bernard
B
Laboratoire de Génétique et Physiologie du Développement, UMR 6545 CNRS-Université, IBDM-CNRS-Université de la Méditerranée, Marseille Cedex 09 13288, France.
Freeman
Matthew
M
Kerridge
Stephen
S
Baonza
Antonio
A
D000818:Animals; D002465:Cell Movement; D004330:Drosophila; D029721:Drosophila Proteins / Q000502:physiology*; D066246:ErbB Receptors / Q000502:physiology*; D005136:Eye Proteins / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D020191:Myoclonic Epilepsies, Progressive / Q000209:etiology / Q000235:genetics; D010786:Photoreceptor Cells / Q000166:cytology; D012097:Repressor Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
C076188:AOP protein, Drosophila; D029721:Drosophila Proteins; D005136:Eye Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C064045:delta protein; C450826:gug protein, Drosophila; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases