The Hedgehog (Hh) family of proteins plays important roles in the determination of neuronal cell fates and the maintenance of adult neural stem cell potentials. Previous studies and our preliminary results indicate that Sonic hedgehog (Shh) promotes retinal progenitor cell proliferation and affects specification of early born retinal neurons. However, the precise function of Hh signaling in mammalian photoreceptor cell development and survival is not well understood. The proposed research will use molecular genetic approaches to elucidate the roles of Hh signaling during mouse photoreceptor development and maintenance. The essential Hh receptor component Smoothened (Smo) will be eliminated by Cre/loxP recombination using transgenic mouse lines and retroviruses expressing Cre recombinase. The effects of disrupting Hh signaling on postnatal progenitor proliferation and cell fate commitment, and on photoreceptor differentiation and morphogenesis will be analyzed using molecular markers and electron microscopy. The roles of Hh signaling in photoreceptor maintenance and survival will be characterized by ablating the Smo gene or the Shh gene in the mature retina followed by functional and morphological analyses. Results of the proposed research will elucidate the function of an important signaling pathway in mammalian photoreceptor differentiation and survival. Moreover, these studies will provide new insights into mechanisms of photoreceptor degeneration and opportunities to develop novel therapies for combating retinal diseases.

Public Health Relevance

The proposed research will study the influence of an important class of proteins called hedgehog on the formation and survival of photoreceptor cells, which undergo degeneration in various retinal diseases. The outcomes of these studies will enhanced our abilities to protect photoreceptor cells and to direct the differentiation of neural stem cells towards functional photoreceptor cells for retinal disease therapy.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019052-04
Application #
8389555
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
2009-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2013
Total Cost
$351,120
Indirect Cost
$123,120
Name
University of California Los Angeles
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Hamon, Annaïg; Roger, Jérôme E; Yang, Xian-Jie et al. (2016) Müller glial cell-dependent regeneration of the neural retina: An overview across vertebrate model systems. Dev Dyn 245:727-38
Xie, Bin-Bin; Zhang, Xiang-Mei; Hashimoto, Takao et al. (2014) Differentiation of retinal ganglion cells and photoreceptor precursors from mouse induced pluripotent stem cells carrying an Atoh7/Math5 lineage reporter. PLoS One 9:e112175
Rhee, Kun Do; Nusinowitz, Steven; Chao, Kevin et al. (2013) CNTF-mediated protection of photoreceptors requires initial activation of the cytokine receptor gp130 in Müller glial cells. Proc Natl Acad Sci U S A 110:E4520-9
Rhee, K-D; Yu, J; Zhao, C Y et al. (2012) Dnmt1-dependent DNA methylation is essential for photoreceptor terminal differentiation and retinal neuron survival. Cell Death Dis 3:e427
Hsieh, Yi-Wen; Yang, Xian-Jie (2012) Transfection of primary embryonic chicken retinal cells using cationic lipid. Methods Mol Biol 884:183-92
Sakagami, Kiyo; Chen, Bryan; Nusinowitz, Steven et al. (2012) PTEN regulates retinal interneuron morphogenesis and synaptic layer formation. Mol Cell Neurosci 49:171-83
Rhee, Kun Do; Yang, Xian-Jie (2010) Function and mechanism of CNTF/LIF signaling in retinogenesis. Adv Exp Med Biol 664:647-54