Abstract

Development of the vertebrate eye is a complex process that requires interaction of several key transcription factors. One of them is the paired-like homeobox-containing gene Rx. Rx belongs to a small, conserved family of genes that displays an almost identical expression pattern in all of the vertebrate species. 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. No markers of eye development are expressed in these embryos suggesting that retinal progenitor cells do not form in the absence of Rx function. Since Rx is a key component in formation of vertebrate eyes, we propose four specific goals related to its function in eye development:
Specific Aim 1 : Analysis of the ability of cells lacking Rx function to contribute to normal retinal structures. For this purpose, we will make chimeric mouse embryos from Rx-/- and wild type cells. This experiment will determine whether Rx-/- cells can contribute to normal eye development in the presence of wild type cells.
Specific Aim 2 : Identification of the molecular mechanism that regulates the spatial and temporal expression of Rx genes. Rx regulatory elements will be identified using reporter constructs.
Specific Aim 3 : Effect of FGF signaling on the specification and survival of retinal cells. For this purpose dominant negative FGF receptors will be expressed in the developing retina using Rx regulatory sequences. Effects of elimination of FGF signaling on the development of retinal cell types will be monitored.
Specific Aim 4 : Manipulation of gene expression in the Xenopus retina in order to study development and differentiation. This will be achieved by a targeted expression of specific proteins in the retinal progenitor cells of transgenic Xenopus using the Rx regulatory region. Specific attention will be paid to the Otx2 and Xbarl homeobox-containing genes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012163-07
Application #
7064773
Study Section
Special Emphasis Panel (ZRG1-VISC (01))
Program Officer
Hunter, Chyren
Project Start
1999-01-01
Project End
2007-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
7
Fiscal Year
2006
Total Cost
$330,668
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
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
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
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

Showing the most recent 10 out of 13 publications