The homeodomain-containing transcription factor Chx10 is a central regulator of retinal development. Much of what we know about Chx10 function comes from studies using ocular retardation J (orJ) mice, which have a null mutation in the Chx10 gene. Work from our laboratory has contributed to an understanding of its role in retinal progenitor cell (RPC) proliferation and cell cycle progression. Additionally, our work and others reveal that Chx10 also influences the timing of neurogenesis, maintains neuroretinal identity, regulates adult retinal stem cells, and is required for bipolar cell formation. The primary goal of our work is to uncover the specific Chx10-dependent molecular mechanisms and pathways driving retinal development. One challenge in achieving this goal is that multiple alterations in RPC properties (assessed in orJ mice) overlap in time and initiate early in retinal development. Because of this, it is not known if these changes are mediated by shared mechanisms and whether Chx10 is required for regulating RPC properties at later stages of development. To resolve these issues and gain insight into molecular mechanisms of Chx10 function, we propose three aims.
In Aim 1, we will perform a series of genetic experiments using a conditional allele of Chx10 and chimeric mice to determine developmental stages when Chx10 required in RPCs and to determine if RPC changes induced by Chx10 loss are due solely to cell-autonomous mechanisms.
In Aims 2 and 3, we investigate two potential mechanisms of Chx10 function.
Aim 2 builds on our recent study of hedgehog signaling indicating that loss of Chx10 influences the efficiency of signaling pathways important for proliferation. Using culture assays and gene expression measurements, we will investigate how Chx10 interacts with the hedgehog pathway.
In Aim 3, we investigate a potential interaction between Chx10 and the homeodomain-containing transcription factor Lhx2 (an essential regulator of early eye development) using genetic approaches in mice. Our studies have the potential to provide a rich map of the complex mechanisms controlling formation of the retina and could provide insights into the refined use of stem cells for treating retinal disease.

Public Health Relevance

Microphthalmia is a congenital anomaly in which the eye fails to grow to its normal size. Ocular malformations, which include microphthalmia are reported to be as high as 1 in 5000 births and children born with these malformations are often severely visually impaired or blind. The goals of the research proposed here are to understand the basis for these defects with the hope of one day developing a restorative treatment or cure for these devastating disabilities.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013760-08
Application #
8204529
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
2001-12-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
8
Fiscal Year
2012
Total Cost
$357,588
Indirect Cost
$119,988
Name
University of Utah
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Fuhrmann, Sabine; Zou, ChangJiang; Levine, Edward M (2014) Retinal pigment epithelium development, plasticity, and tissue homeostasis. Exp Eye Res 123:141-50
Gordon, Patrick J; Yun, Sanghee; Clark, Anna M et al. (2013) Lhx2 balances progenitor maintenance with neurogenic output and promotes competence state progression in the developing retina. J Neurosci 33:12197-207
Das, Gaurav; Clark, Anna M; Levine, Edward M (2012) Cyclin D1 inactivation extends proliferation and alters histogenesis in the postnatal mouse retina. Dev Dyn 241:941-52
Vazquez-Chona, Felix R; Swan, Alex; Ferrell, W Drew et al. (2011) Proliferative reactive gliosis is compatible with glial metabolic support and neuronal function. BMC Neurosci 12:98
Yun, Sanghee; Saijoh, Yukio; Hirokawa, Karla E et al. (2009) Lhx2 links the intrinsic and extrinsic factors that control optic cup formation. Development 136:3895-906
Das, Gaurav; Choi, Yoon; Sicinski, Piotr et al. (2009) Cyclin D1 fine-tunes the neurogenic output of embryonic retinal progenitor cells. Neural Dev 4:15
Sigulinsky, Crystal L; Green, Eric S; Clark, Anna M et al. (2008) Vsx2/Chx10 ensures the correct timing and magnitude of Hedgehog signaling in the mouse retina. Dev Biol 317:560-75
Barton, Kirston M; Levine, Edward M (2008) Expression patterns and cell cycle profiles of PCNA, MCM6, cyclin D1, cyclin A2, cyclin B1, and phosphorylated histone H3 in the developing mouse retina. Dev Dyn 237:672-82
Clark, Anna M; Yun, Sanghee; Veien, Eric S et al. (2008) Negative regulation of Vsx1 by its paralog Chx10/Vsx2 is conserved in the vertebrate retina. Brain Res 1192:99-113
Defoe, Dennis M; Adams, Lorrie B S; Sun, Jingru et al. (2007) Defects in retinal pigment epithelium cell proliferation and retinal attachment in mutant mice with p27(Kip1) gene ablation. Mol Vis 13:273-86

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