The eyes absent (eya) and sine oculis (so) genes in Drosophila are key components of the retinal determination (RD) network, which is essential for normal development in both flies and vertebrates. Eya functions both as a transcriptional coactivator and a protein phosphatase while so encodes a homeodomain transcription factor. Both genes are necessary and sufficient for retinal development in Drosophila. Moreover, the Eya and So proteins physically interact and act synergistically as a highly potent transcription complex that regulates development of several organ systems. Two highly conserved homologs of so, Six3 and Six6, are required for normal retinal development in vertebrates. In humans, mutations in EYA1 and SIX1 cause the autosomal dominant disorder known as BOR (branchio-oto-renal) syndrome, characterized by branchial arch abnormalities, hearing loss, and kidney defects. Despite their importance during mammalian development, the mechanism of Eya and So action remains incompletely understood. In addition, Eya and So directly regulate atonal and senseless, which are required for the first steps in photoreceptor cell differentiation and are highly conserved in mammals. Two other conserved transcriptional regulators required for normal retinal differentiation, Lozenge and Groucho, also appear to be directly regulated by So. Thus, Eya and So mediate the transition from determination to differentiation and thereby act at a critical junction in organogenesis. Our proposal focuses on understanding the role of these six genes in a well-characterized genetic system, the Drosophila eye. We will use a combination of genetics, genomics, and biochemistry to analyze the roles of Eya and So, as well as Ato, Sens, Lozenge, and Groucho, during retinal development. Since genetic pathways are often conserved and reiteratively used during organ formation across phylogeny, studying the development of simpler organisms can provide rapid and significant insight into human disease.

Public Health Relevance

The main goal of this project is to understand how the eyes absent (eya) and sine oculis (so) genes act during eye development. Both genes are highly conserved from fruit flies to humans and are known to play essential roles in human development, including the eye. We will use the unparalleled power of Drosophila genetics to decipher the function of these important but poorly understood genes.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011232-16
Application #
8317674
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
1996-02-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
16
Fiscal Year
2012
Total Cost
$364,716
Indirect Cost
$127,116
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Karandikar, Umesh C; Jin, Meng; Jusiak, Barbara et al. (2014) Drosophila eyes absent is required for normal cone and pigment cell development. PLoS One 9:e102143
Jusiak, Barbara; Wang, Feng; Karandikar, Umesh C et al. (2014) Genome-wide DNA binding pattern of the homeodomain transcription factor Sine oculis (So) in the developing eye of Drosophila melanogaster. Genom Data 2:153-155
Jusiak, Barbara; Karandikar, Umesh C; Kwak, Su-Jin et al. (2014) Regulation of Drosophila eye development by the transcription factor Sine oculis. PLoS One 9:e89695
Atkins, Mardelle; Jiang, Yuwei; Sansores-Garcia, Leticia et al. (2013) Dynamic rewiring of the Drosophila retinal determination network switches its function from selector to differentiation. PLoS Genet 9:e1003731
Jin, Meng; Jusiak, Barbara; Bai, Zengliang et al. (2013) Eyes absent tyrosine phosphatase activity is not required for Drosophila development or survival. PLoS One 8:e58818
Haase Gilbert, Erin; Kwak, Su-Jin; Chen, Rui et al. (2013) Drosophila signal peptidase complex member Spase12 is required for development and cell differentiation. PLoS One 8:e60908
Jiang, Y; Scott, K L; Kwak, S-J et al. (2011) Sds22/PP1 links epithelial integrity and tumor suppression via regulation of myosin II and JNK signaling. Oncogene 30:3248-60
Anderson, Aimee E; Karandikar, Umesh C; Pepple, Kathryn L et al. (2011) The enhancer of trithorax and polycomb gene Caf1/p55 is essential for cell survival and patterning in Drosophila development. Development 138:1957-66
Atkins, Mardelle; Mardon, Graeme (2009) Signaling in the third dimension: the peripodial epithelium in eye disc development. Dev Dyn 238:2139-48
Pepple, Kathryn L; Atkins, Mardelle; Venken, Koen et al. (2008) Two-step selection of a single R8 photoreceptor: a bistable loop between senseless and rough locks in R8 fate. Development 135:4071-9

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