Development of the vertebrate eye requires a series of developmental events that lead to the formation of the retina and the lens, which are collectively called the eyeball. In addition to the eyeball, eye-associated structures such as the cornea, lacrimal gland, eyelid and conjunctiva are made that are required for the proper function of the eyeball. Our long-term goal is to identify developmental steps and molecular events necessary for the correct formation of each individual vertebrate eye structure. In this project, we are focusing on the development of anterior eye structures, with the primary aim to understand lens development. This proposal is a natural continuation of our previous studies investigating the role of the forkhead box-containing gene Foxe3 in lens formation, and the role of the homeobox-containing gene Rx in retinal formation. We propose the following specific aims for the next five years:
Specific Aim 1 is to determine the developmental fate and gene expression of the head surface ectoderm in the absence of the retina. In wild type embryos, the lateral head surface ectoderm develops into the lens and auxiliary eye structures. In Rx-/- embryos, which have no retinal structures, the lens does not develop. The unanswered question remains whether auxiliary eye structures develop in the absence of the retina and the lens. For this reason, in the first part of specific aim 1, we will determine whether auxiliary eye structures develop in Rx-/- embryos. In the second part of this specific aim, we will characterize gene expression in lateral head surface ectoderm in the absence of the retina and compare it to gene expression in the head surface ectoderm of wild type embryos. This comparison will identify the changes in gene expression that are orchestrated by the retina, and lead to lens formation.
Specific Aim 2 is to study the functional significance of the observed changes in gene expression in head surface ectoderm in the presence and absence of the retina. For this purpose, we will modify gene expression in the head surface ectoderm of Rx-/- animals and will monitor lens induction, as well as lens-specific gene expression. Formation of a lens placode will be viewed as the establishment of lens fate, and the expression of Foxe3, as the establishment of lens-specific gene expression.
Specific Aim 3 is to correct the molecular and phenotypic defects in mice with mutant Foxe3 function by intrauterine gene transfer. For this purpose, we will introduce the wild type Foxe3 gene into dysgenetic lens embryos using viral vectors. These vectors will carry the Foxe3 regulatory and coding sequences of the wild type gene and will be delivered to the mutant embryos via intrauterine gene transfer. The goal of this project is to identify genes and developmental processes that are responsible for normal eye development. Identification of these genes and developmental processes will lead to the better understanding of eye diseases. As a result, new diagnostic procedures and treatments for eye diseases will be developed.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012505-09
Application #
7924086
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Araj, Houmam H
Project Start
2000-02-01
Project End
2011-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
9
Fiscal Year
2010
Total Cost
$578,277
Indirect Cost
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
Shibata, Maho; Ishizaki, Eisuke; Zhang, Ting et al. (2018) Purinergic Vasotoxicity: Role of the Pore/Oxidant/KATP Channel/Ca2+ Pathway in P2X7-Induced Cell Death in Retinal Capillaries. Vision (Basel) 2:
Bankhead, Elizabeth J; Colasanto, Mary P; Dyorich, Kayla M et al. (2015) Multiple requirements of the focal dermal hypoplasia gene porcupine during ocular morphogenesis. Am J Pathol 185:197-213
Fukumoto, Masanori; Nakaizumi, Atsuko; Zhang, Ting et al. (2012) Vulnerability of the retinal microvasculature to oxidative stress: ion channel-dependent mechanisms. Am J Physiol Cell Physiol 302:C1413-20
Nakaizumi, Atsuko; Zhang, Ting; Puro, Donald G (2012) The electrotonic architecture of the retinal microvasculature: diabetes-induced alteration. Neurochem Int 61:948-53
Puro, Donald G (2012) Retinovascular physiology and pathophysiology: new experimental approach/new insights. Prog Retin Eye Res 31:258-70
Nakaizumi, Atsuko; Puro, Donald G (2011) Vulnerability of the retinal microvasculature to hypoxia: role of polyamine-regulated K(ATP) channels. Invest Ophthalmol Vis Sci 52:9345-52
Zhang, Ting; Wu, David M; Xu, Ge-Zhi et al. (2011) The electrotonic architecture of the retinal microvasculature: modulation by angiotensin II. J Physiol 589:2383-99
Matsushita, Kenji; Fukumoto, Masanori; Kobayashi, Takatoshi et al. (2010) Diabetes-induced inhibition of voltage-dependent calcium channels in the retinal microvasculature: role of spermine. Invest Ophthalmol Vis Sci 51:5979-90
Ishizaki, Eisuke; Fukumoto, Masanori; Puro, Donald G (2009) Functional K(ATP) channels in the rat retinal microvasculature: topographical distribution, redox regulation, spermine modulation and diabetic alteration. J Physiol 587:2233-53
Medina-Martinez, Olga; Shah, Rina; Jamrich, Milan (2009) Pitx3 controls multiple aspects of lens development. Dev Dyn 238:2193-201

Showing the most recent 10 out of 48 publications