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
Spratford, Carrie M; Kumar, Justin P (2014) Hedgehog and extramacrochaetae in the Drosophila eye: an irresistible force meets an immovable object. Fly (Austin) 8:36-42
Anderson, Abigail M; Weasner, Brandon P; Weasner, Bonnie M et al. (2014) The Drosophila Wilms? Tumor 1-Associating Protein (WTAP) homolog is required for eye development. Dev Biol 390:170-80
Spratford, Carrie M; Kumar, Justin P (2014) Dissection and immunostaining of imaginal discs from Drosophila melanogaster. J Vis Exp :51792
Weasner, Bonnie M; Kumar, Justin P (2013) Competition among gene regulatory networks imposes order within the eye-antennal disc of Drosophila. Development 140:205-15
Spratford, Carrie M; Kumar, Justin P (2013) Extramacrochaetae imposes order on the Drosophila eye by refining the activity of the Hedgehog signaling gradient. Development 140:1994-2004
Kumar, Justin P (2012) Building an ommatidium one cell at a time. Dev Dyn 241:136-49
Anderson, Abigail M; Weasner, Bonnie M; Weasner, Brandon P et al. (2012) Dual transcriptional activities of SIX proteins define their roles in normal and ectopic eye development. Development 139:991-1000
Datta, Rhea R; Cruickshank, Tami; Kumar, Justin P (2011) Differential selection within the Drosophila retinal determination network and evidence for functional divergence between paralog pairs. Evol Dev 13:58-71
Salzer, Claire L; Elias, Yair; Kumar, Justin P (2010) The retinal determination gene eyes absent is regulated by the EGF receptor pathway throughout development in Drosophila. Genetics 184:185-97
Salzer, Claire L; Kumar, Justin P (2010) Identification of retinal transformation hot spots in developing Drosophila epithelia. PLoS One 5:e8510

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