The early development of a number of insect and mammalian tissues including the eye requires 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 early formation and initial patterning of the retina. The function of these two gene families are highly significant to human health as mutations can lead to holoprosencephaly with associated cyclopia, bilateral anophthalmia and 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 are homeobox containing transcription factors whereas EYA proteins have transcriptional co-activator and protein tyrosine phosphatase activities. These proteins regulate the transcription of target genes as SIX-EYA heterodimers. Disruption of these complexes, in addition to causing retinal disorders in both mouse models and human patients, leads to a complete block in retinal development in Drosophila melanogaster. The fruit fly eye has become a premier model system for studying the genetic and molecular mechanisms that govern tissue determination. We will take advantage of the no-eye phenotypes caused by mutations in the sine oculis (so) and eyes absent (eya) genes (the founding members of the SIX and Eya gene families) to investigate novel activities of the So-Eya complex. The ability of this complex to also coax non-ocular tissue into adopting an eye fate (ectopic eyes) is another tool that can be utilized to dissect the roles that these proteins play in early retinal determination and patterning. In this application I propose to (1) study a novel mechanism by which the So-Eya complex represses transcription of non-ocular selector genes during early eye formation;(2) identify transcription factors that bind to and activate recently identified novel enhancers of the eya gene;and (3) determine the molecular and functional relationships between the So-Eya complex and the Decapentaplegic (Dpp) signaling pathway. The association of SIX and EYA gene lesions with retinal disorders in both insect and mammalian systems provides us with an exciting opportunity for studies in the Drosophila eye to advance our understanding of mammalian eye formation and human retinal disorders.

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. Mutations in these genes lead to several multi-organ disorders including congenital cataracts, anophthalmia, holoprosencephaly, myotonic dystrophy and branchio-oto-renal syndrome. This work will lead to insights into how the So and Eya genes guide cells within the visual primordium to correctly adopt a retinal fate.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY014863-09A1
Application #
8694777
Study Section
Special Emphasis Panel (BVS)
Program Officer
Greenwell, Thomas
Project Start
2003-08-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
9
Fiscal Year
2014
Total Cost
$390,000
Indirect Cost
$140,000
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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