Our long-term goal is to identify and understand the molecular and cellular pathways involved in retinal organization, and photoreceptor morphogenesis and survival. We are studying the mosaic eyes (moe) gene in zebrafish; mutations in moe cause a failure of retinal lamination and defects in the retinal pigmented epithelial (RPE). We found that retinal epithelial cells are also improperly organized; in moe- retinas they divide throughout the epithelium instead of being localized to apical (RPE) surface. We showed by generating genetic mosaics that moe function is required in the RPE for the proper localization of adjacent retinal cell divisions rather then being required in the retinal cells themselves (Jensen et al., 2001). We cloned the moe locus and it encodes a novel FERM protein (for 4.1 protein, Ezrin, Radixin, Moesin). We provide preliminary evidence that moe acts in the crumbs pathway of apical cell polarity. Mutations in the human Crumbs homologue 1 (Crbl) gene are associated with two severe and early onset retinal degeneration diseases, retinitis pigmentosa 12 (RP12; den Hollander et al., 1999) and Leber's Congenital Amaurosis 1 (LCA1; den Hollander et al., 2001a). Recent work using high-resolution microscopy in vivo, has revealed that the retinas of LCA1 patients are abnormally laminated, a phenotype remarkably similar to the moe mutations. We will test the hypothesis that Moe interacts directly with Crumbs proteins. In Drosophila, crumbs is necessary for photoreceptor morphogenesis (Izaddoost et al., 2002; Pellikka et al., 2002) and the early and severe onset of RP12 may suggest it plays a similar role in vertebrate photoreceptor morphogenesis. Zebrafish moe is expressed in the retina like crbl, suggesting it may cooperate with crbl in photoreceptor morphogenesis. We will test the hypothesis that moe is required for normal photoreceptor morphogenesis. Finally, we will test the hypothesis that moe is required in the RPE for normal retinal lamination.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY015420-02
Application #
6877690
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Mariani, Andrew P
Project Start
2004-04-01
Project End
2008-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
2
Fiscal Year
2005
Total Cost
$307,406
Indirect Cost
Name
University of Massachusetts Amherst
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003