Abstract

Vertebrate eye formation is a complex process that requires specification of the anterior neural plate, formation of the optic vesicle, and cellular differentiation of the lens and retina. Each of these developmental processes is likely to be mediated by an interaction of transcriptional regulators, growth factors and their receptors. It is the goal of this research to identify genes and processes that play a critical role in the initial stages of eye formation. Specific emphasis will be placed on the role of the homeobox gene Rx in the formation of retinal progenitor cells and in the maintenance of retinal stem cells. We have found that Rx is essential for normal eye development and its misexpression has profound effects on eye morphology. Xenopus embryos injected with Rx RNA develop ectopic retinal tissue and display hyperproliferation in the neuroretina. Mouse embryos carrying a null allele of this gene do not form optic cups and consequently do not develop eyes. Given the vital role of Rx during eye development, we propose three specific goals related to its function during retinal formation:
Specific aim 1 : Study of the Rx regulatory pathway. This will be achieved by analyzing gene expression in Xenopus embryos and animal caps injected with Rx RNA and by analyzing gene expression in Rx null mouse mutant.
Specific aim 2 : Characterization of sequences that direct Rx expression into the retinal progenitor cells and retinal stem cells. For this purpose we will ligate the 5' flanking regions of the Rx gene to Beta-galactosidase reporter system. Transgenic mice made using this construct will be monitored for eye specific expression of Beta-galactosidase.
Specific aim 3 : Immortalization of retinal stem cells. Retinal stem cells will be immortalized either by fusing Rx regulatory sequences to the SV40 T antigen or by linking Rx coding sequences to a constitutively activated promoter. This research is of importance for better understanding of normal and abnormal eye development such as anophthalmia and microphthalmia, and is likely to provide us with information necessary for replacement of retinal cells in degenerative eye diseases using retinal stem cell population.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012163-03
Application #
6342665
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Hunter, Chyren
Project Start
1999-01-01
Project End
2002-12-31
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
3
Fiscal Year
2001
Total Cost
$294,972
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Medina-Martinez, Olga; Shah, Rina; Jamrich, Milan (2009) Pitx3 controls multiple aspects of lens development. Dev Dyn 238:2193-201
Medina-Martinez, Olga; Amaya-Manzanares, Felipe; Liu, Chaomei et al. (2009) Cell-autonomous requirement for rx function in the mammalian retina and posterior pituitary. PLoS One 4:e4513
McLin, Valerie A; Hu, Cheng-Hui; Shah, Rina et al. (2008) Expression of complement components coincides with early patterning and organogenesis in Xenopus laevis. Int J Dev Biol 52:1123-33
Swindell, Eric C; Liu, Chaomei; Shah, Rina et al. (2008) Eye formation in the absence of retina. Dev Biol 322:56-64
Swindell, Eric C; Zilinski, Carolyn A; Hashimoto, Ryuju et al. (2008) Regulation and function of foxe3 during early zebrafish development. Genesis 46:177-83
Swindell, Eric C; Bailey, Travis J; Loosli, Felix et al. (2006) Rx-Cre, a tool for inactivation of gene expression in the developing retina. Genesis 44:361-3
Zilinski, Carolyn A; Shah, Rina; Lane, Mary Ellen et al. (2005) Modulation of zebrafish pitx3 expression in the primordia of the pituitary, lens, olfactory epithelium and cranial ganglia by hedgehog and nodal signaling. Genesis 41:33-40
Medina-Martinez, Olga; Brownell, Isaac; Amaya-Manzanares, Felipe et al. (2005) Severe defects in proliferation and differentiation of lens cells in Foxe3 null mice. Mol Cell Biol 25:8854-63
Offner, Nicolas; Duval, Nathalie; Jamrich, Milan et al. (2005) The pro-apoptotic activity of a vertebrate Bar-like homeobox gene plays a key role in patterning the Xenopus neural plate by limiting the number of chordin- and shh-expressing cells. Development 132:1807-18
Yatsenko, Alexander N; Wiszniewski, Wojciech; Zaremba, Charles M et al. (2005) Evolution of ABCA4 proteins in vertebrates. J Mol Evol 60:72-80

Showing the most recent 10 out of 13 publications