The long-term goal of this research is to elucidate the mechanisms whereby cells integrate instructions from multiple signaling pathways and respond in a context-appropriate manner. In this context, post-translational modifications such as phosphorylation and dephosphorylation provide versatile strategies for dynamically modulating transcription factor activity in response to specific signaling inputs. However the mechanisms whereby such modifications coordinately regulate transcription factor function, interactions with the basal transcription machinery, and alterations in chromatin structure to achieve a context-specific output remain poorly understood. Drosophila is particularly well-suited to addressing complex developmental questions because of the ease with which genetic, molecular, biochemical, cell biological and genomic approaches can be combined. Because developmental signaling mechanisms have been highly conserved in evolution, knowledge of the molecular circuitries used in Drosophila will fundamentally advance our understanding of how cell fates are designated and maintained, and why misregulation results in cancer and disease in mammals. ? ? This proposal addresses the hypothesis that nuclear tyrosine phosphatase activity, mediated by a dual function transcription factor and phosphatase, provides a novel strategy for transcriptional regulation and signal integration.
The specific aims are to define a new function for the transcriptional coactivator Eyes absent as a phosphatase, to determine how phosphatase activity is regulated and coordinated with transcriptional functions, and to investigate the physiological context in which Eyes absent participates in nuclear phosphorylation and dephosphorylation events. Given the extent of evolutionary conservation of the proteins studied in this proposal, this work will provide novel insights into fundamental signaling mechanisms underlying human development and disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012549-09
Application #
7126815
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Mariani, Andrew P
Project Start
1999-05-03
Project End
2008-04-30
Budget Start
2006-07-01
Budget End
2007-04-30
Support Year
9
Fiscal Year
2006
Total Cost
$374,732
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Davis, Trevor L; Rebay, Ilaria (2018) Pleiotropy in Drosophila organogenesis: Mechanistic insights from Combgap and the retinal determination gene network. Fly (Austin) 12:62-70
Webber, Jemma L; Zhang, Jie; Massey, Alex et al. (2018) Collaborative repressive action of the antagonistic ETS transcription factors Pointed and Yan fine-tunes gene expression to confer robustness in Drosophila. Development 145:
Davis, Trevor L; Rebay, Ilaria (2017) Antagonistic regulation of the second mitotic wave by Eyes absent-Sine oculis and Combgap coordinates proliferation and specification in the Drosophila retina. Development 144:2640-2651
Davis, Trevor L; Hoi, Charlene S L; Rebay, Ilaria (2017) Mutations that impair Eyes absent tyrosine phosphatase activity in vitro reduce robustness of retinal determination gene network output in Drosophila. PLoS One 12:e0187546
Davis, Trevor L; Rebay, Ilaria (2017) Master regulators in development: Views from the Drosophila retinal determination and mammalian pluripotency gene networks. Dev Biol 421:93-107
Hoi, Charlene S L; Xiong, Wenjun; Rebay, Ilaria (2016) Retinal Axon Guidance Requires Integration of Eya and the Jak/Stat Pathway into Phosphotyrosine-Based Signaling Circuitries in Drosophila. Genetics 203:1283-95
Rebay, Ilaria (2016) Multiple Functions of the Eya Phosphotyrosine Phosphatase. Mol Cell Biol 36:668-77
Zhou, Qingxiang; Zhang, Tianyi; Jemc, Jennifer C et al. (2014) Onset of atonal expression in Drosophila retinal progenitors involves redundant and synergistic contributions of Ey/Pax6 and So binding sites within two distant enhancers. Dev Biol 386:152-64
Xiong, Wenjun; Morillo, Santiago A; Rebay, Ilaria (2013) The Abelson tyrosine kinase regulates Notch endocytosis and signaling to maintain neuronal cell fate in Drosophila photoreceptors. Development 140:176-84
Morillo, Santiago A; Braid, Lorena R; Verheyen, Esther M et al. (2012) Nemo phosphorylates Eyes absent and enhances output from the Eya-Sine oculis transcriptional complex during Drosophila retinal determination. Dev Biol 365:267-76

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