The long-term goal of this project is to improve our ability to prevent, diagnose and treat human retinal diseases. Our experimental approach uses the fruit fly Drosophila melanogaster as an animal model system to identify and determine the function of conserved genes that are required for normal retinal cell fate determination and differentiation. Our studies have focused on a group of retinal determination (RD) genes that encode nuclear proteins that function together in complexes to control gene transcription and retinal cell fates. Each of the RD genes, including eyeless, eyes absent, sine oculis and dachshund, is highly conserved in mammals. We have shown that dachshund (dac) is both necessary and sufficient for normal retinal development in Drosophila. That is, in the absence of dac function, flies develop with no eyes. Moreover, targeted expression of dac leads to the induction of properly formed ectopic eyes on the antennae, legs and thorax. These ectopic eyes contain all of the cell types found in the normal fly eye. Thus, dac functions near the top of the genetic hierarchy controlling retinal development in Drosophila. Importantly, dac is highly conserved in mice and humans and is strongly expressed in the mouse neural retina throughout development. In addition, we are investigating how the highly conserved general signaling pathways, such as hedgehog and the TGFI3 homolog dpp, are integrated with the function of the RD genes to control patterning and cell fate determination in the retina. Our continuing studies on the molecular and genetic mechanisms of RD gene function are therefore important steps toward understanding normal retinal development in humans. In addition, we have isolated and are studying Drosophila homologs of two new vertebrate genes that are key players in retinal development.
Our specific aims are to: (1) dissect dac regulatory elements and identify genes directly controlling dac expression; (2) conduct structure/function studies and genetic screens to decipher dac function; (3) integrate the hedgehog signaling pathway with the retinal determination network; and (4) analyze the function of new, conserved genes required for normal retinal development. These studies are designed to further elucidate the molecular and genetic mechanisms controlling retinal cell fate determination in Drosophila, the most powerful genetic model system available. Since all of the genes we study are highly conserved in humans, this work will directly impact our understanding of human retinal development.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011232-06
Application #
6384657
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Hunter, Chyren
Project Start
1996-02-01
Project End
2003-03-21
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
6
Fiscal Year
2001
Total Cost
$261,625
Indirect Cost
Name
Baylor College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Jin, Meng; Mardon, Graeme (2016) Distinct Biochemical Activities of Eyes absent During Drosophila Eye Development. Sci Rep 6:23228
Jin, Meng; Eblimit, Aiden; Pulikkathara, Merlyn et al. (2016) Conditional knockout of retinal determination genes in differentiating cells in Drosophila. FEBS J 283:2754-66
Jin, Meng; Aibar, Sara; Ge, Zhongqi et al. (2016) Identification of novel direct targets of Drosophila Sine oculis and Eyes absent by integration of genome-wide data sets. Dev Biol 415:157-167
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
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
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
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
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
Li, Yumei; Jiang, Yuwei; Chen, Yiyun et al. (2013) optix functions as a link between the retinal determination network and the dpp pathway to control morphogenetic furrow progression in Drosophila. Dev Biol 381:50-61

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