title: Retinal Axon Guidance Requires Integration of Eya and the Jak/Stat Pathway into Phosphotyrosine-Based Signaling Circuitries in Drosophila.
abstract: The transcriptional coactivator and phosphatase eyes absent (Eya) is dynamically compartmentalized between the nucleus and cytoplasm. Although the nuclear transcriptional circuits within which Eya operates have been extensively characterized, understanding of its cytoplasmic functions and interactions remains limited. Our previous work showed that phosphorylation of Drosophila Eya by the Abelson tyrosine kinase can recruit Eya to the cytoplasm and that eya-abelson interactions are required for photoreceptor axons to project to correct layers in the brain. Based on these observations, we postulated that photoreceptor axon targeting might provide a suitable context for identifying the cytoplasmic signaling cascades with which Eya interacts. Using a dose-sensitive eya misexpression background, we performed an RNA interference-based genetic screen to identify suppressors. Included among the top 10 hits were nonreceptor tyrosine kinases and multiple members of the Jak/Stat signaling network (hop, Stat92E, Socs36E, and Socs44A), a pathway not previously implicated in axon targeting. Individual loss-of-function phenotypes combined with analysis of axonal projections in Stat92E null clones confirmed the importance of photoreceptor autonomous Jak/Stat signaling. Experiments in cultured cells detected cytoplasmic complexes between Eya and Hop, Socs36E and Socs44A; the latter interaction required both the Src homology 2 motif in Socs44A and tyrosine phosphorylated Eya, suggesting direct binding and validating the premise of the screen. Taken together, our data provide new insight into the cytoplasmic phosphotyrosine signaling networks that operate during photoreceptor axon guidance and suggest specific points of interaction with Eya.
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Illinois 60637 Committee on Genetics, Genomics, and Systems Biology, University of Chicago, Illinois 60637.
authors.forename: Charlene S L
authors.initials: CS
authors.lastname: Hoi
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Illinois 60637 Committee on Cancer Biology, University of Chicago, Illinois 60637.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Illinois 60637 irebay@uchicago.edu.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Rebay
mesh_terms: D000818:Animals; D000071437:Axon Guidance / Q000235:genetics*; D001369:Axons / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000096:biosynthesis / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development; D005136:Eye Proteins / Q000096:biosynthesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D053612:Janus Kinases / Q000235:genetics; D010766:Phosphorylation; D010786:Photoreceptor Cells / Q000378:metabolism; D012160:Retina / Q000254:growth & development / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; D005136:Eye Proteins; D050791:STAT Transcription Factors; C092694:eya protein, Drosophila; D053612:Janus Kinases
keywords: SH2; Socs44A; eye development; genetic screen; retinal determination network