The early development of a number of mammalian tissues including the eye depends in part upon the activity of an evolutionarily conserved regulatory circuit that includes members of the Pax, Six, Eya and Dach gene families. Of particular interest to this proposal is the role that the Six and Eya proteins play in the retina. The function of these gene families are highly significant as mutations in select genes can lead to holoprosencephaly, bilateral anophthalmia, congenital cataracts as well as non-retinal defects such as myotonic dystrophy and branchio-oto-renal syndrome. Furthermore, these genes are also implicated in tumorigenesis and numerous cancers. Six proteins serve as homeobox containing transcription factors while Eya proteins function as transcriptional co- activators and as protein tyrosine phosphatases. These protein families cooperate by forming Six-Eya heterodimers that are thought to function as strong activators of downstream target genes. The activity of these heterodimers is crucial as loss-of-function mutations can lead to retinal defects in human patients and mouse model systems as well as total elimination of the compound eyes of the fruit fly, Drosophila melanogaster. The association of Six and Eya gene lesions with retinal disorders in both insect and mammalian systems provides us with an exciting opportunity to further explore the roles that these factors play in retinogenesis. The developing eye of the fruit fly has become a premier model system for studying the genetic and molecular mechanisms that govern tissue determination. The advantages include a stereotyped mode of development that has been well described, a large body of experimental data on known eye specification genes and a vast array of available mutant strains and molecular/cellular markers. In Drosophila, eyes absent is the sole member of the Eya family while sine oculis, optix and DSix4 represent the Six gene family. Despite the significant efforts that have been placed on understanding the roles that these genes play in development there are a large number of important questions that still remain unanswered. The goals of the proposed work are to address these questions and provide answers that will further our understanding of role played by Six and Eya genes in retinal determination. In this proposal we will attempt to determine (1) the role that optix plays in normal eye development;(2) the part that sine oculis and eyes absent plays in linking retinal specification to the cell cycle and tissue growth;and (3) the identity of the transcriptional targets of Sine Oculis during eye specification and the influence that it has on their regulation. In order to address these issues we will use a creative mixture of genetic, molecular and biochemical approaches along with genomic and bioinformatic methods to investigate these issues.

Public Health Relevance

The early development of many mammalian tissues including the human retina is governed in part by the activities of a molecular circuit that includes members of the Six and Eya gene families. This work will yields insights into how these genes guide cells within the visual primordium to correctly adopt a retinal fate. Our studies may also provide clues to how cells react at the molecular level to the loss of the Six and Eya genes.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY014863-08
Application #
8265287
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
2003-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$369,600
Indirect Cost
$129,600
Name
Indiana University Bloomington
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
Baker, Luke R; Weasner, Bonnie M; Nagel, Athena et al. (2018) Eyeless/Pax6 initiates eye formation non-autonomously from the peripodial epithelium. Development 145:
Zhu, Jinjin; Ordway, Alison J; Weber, Lena et al. (2018) Polycomb group (PcG) proteins and Pax6 cooperate to inhibit in vivo reprogramming of the developing Drosophila eye. Development 145:
Palliyil, Sneha; Zhu, Jinjin; Baker, Luke R et al. (2018) Allocation of distinct organ fates from a precursor field requires a shift in expression and function of gene regulatory networks. PLoS Genet 14:e1007185
Kumar, Justin P (2018) The fly eye: Through the looking glass. Dev Dyn 247:111-123
Zhu, Jinjin; Palliyil, Sneha; Ran, Chen et al. (2017) Drosophila Pax6 promotes development of the entire eye-antennal disc, thereby ensuring proper adult head formation. Proc Natl Acad Sci U S A 114:5846-5853
Weasner, Bonnie M; Zhu, Jinjin; Kumar, Justin P (2017) FLPing Genes On and Off in Drosophila. Methods Mol Biol 1642:195-209
Iyer, Janani; Wang, Qingyu; Le, Thanh et al. (2016) Quantitative Assessment of Eye Phenotypes for Functional Genetic Studies Using Drosophila melanogaster. G3 (Bethesda) 6:1427-37
Weasner, Bonnie M; Weasner, Brandon P; Neuman, Sarah D et al. (2016) Retinal Expression of the Drosophila eyes absent Gene Is Controlled by Several Cooperatively Acting Cis-regulatory Elements. PLoS Genet 12:e1006462
Spratford, Carrie M; Kumar, Justin P (2015) Extramacrochaetae functions in dorsal-ventral patterning of Drosophila imaginal discs. Development 142:1006-15
Spratford, Carrie M; Kumar, Justin P (2015) Inhibition of Daughterless by Extramacrochaetae mediates Notch-induced cell proliferation. Development 142:2058-68

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