Retinoic acid (RA), a metabolic derivative of vitamin A (retinol), is essential for axial patterning of the eye during vertebrate development. Retinoid signaling occurs when retinol is metabolized to retinal and then to RA which serves as a ligand for nuclear retinoid receptors that regulate gene expression. Disruption of retinoid signaling either by gestational vitamin A deficiency or by creation of retinoid receptor null mutations results in abnormal dorsoventral axial development of the eye. The mechanism for generation of RA locally in the eye as well as the mechanism for how RA regulates dorsoventral patterning of the eye are not yet understood. Our understanding of how retinol is physiologically activated to form RA is still vague, but has been improved by discovery of three retinoid dehydrogenases expressed in the eye that metabolize retinal to RA, i.e. RALDH1, RALDH2, and RALDH3, all members of the aldehyde dehydrogenase (ALDH) enzyme family. Raldh2 null mutant mice generated in this laboratory and another have revealed phenotypes that are lethal at midgestation with massive trunk and forelimb developmental defects plus abnormal hindbrain patterning, but no optic vesicle defects were observed. Maternal RA administration rescues many defects in Raldh2 mutants, thus allowing further analysis by conditional rescue. Raldh1 null mutant mice recently generated in this laboratory are viable, but embryos suffer a lack of RA synthesis in the dorsal retina suggesting that retinal defects will be discovered upon further analysis. There have been no genetic studies reported on Raldh3. Further analysis of RALDHs should provide key information needed to understand human developmental eye defects. The overall goals of this project are to use null mutant mice to establish roles for RALDH1, RALDH2, and RALDH3 in eye RA synthesis, plus use these mutant mice as tools to further examine the mechanism of retinoid signaling in eye development. Mutant mice will be examined for developmental eye defects histologically and by in situ hybridization to detect disrupted gene expression in eye tissues. Mice carrying the RARE-lacZ marker gene will be used to detect endogenous RA in mutant embryos. Specific goals for this project will be as follows: (1) Use Raldh1 mutants to examine the effect of a lack of RA in the dorsal retina on retinal development and axonal pathfinding for retinofugal projections; (2) Examine the contribution of RALDH1 and RALDH2 to RA synthesis for eye development by comparison of conditionally RA-rescued Raldh2 mutants and Raldh1-Raldh2 double mutants; (3) Generate Raldh3 null mutant mice to examine the role of this gene in eye development.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY013969-02
Application #
6622890
Study Section
Special Emphasis Panel (ZRG1-VISC (01))
Program Officer
Hunter, Chyren
Project Start
2002-04-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$445,500
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Yasmeen, Rumana; Reichert, Barbara; Deiuliis, Jeffrey et al. (2013) Autocrine function of aldehyde dehydrogenase 1 as a determinant of diet- and sex-specific differences in visceral adiposity. Diabetes 62:124-36
Kumar, Sandeep; Sandell, Lisa L; Trainor, Paul A et al. (2012) Alcohol and aldehyde dehydrogenases: retinoid metabolic effects in mouse knockout models. Biochim Biophys Acta 1821:198-205
Chatzi, Christina; Brade, Thomas; Duester, Gregg (2011) Retinoic acid functions as a key GABAergic differentiation signal in the basal ganglia. PLoS Biol 9:e1000609
Anderson, David W; Schray, Rebecca C; Duester, Gregg et al. (2011) Functional significance of aldehyde dehydrogenase ALDH1A1 to the nigrostriatal dopamine system. Brain Res 1408:81-7
Reichert, Barbara; Yasmeen, Rumana; Jeyakumar, Shanmugam M et al. (2011) Concerted action of aldehyde dehydrogenases influences depot-specific fat formation. Mol Endocrinol 25:799-809
Crandall, James E; Goodman, Timothy; McCarthy, Deirdre M et al. (2011) Retinoic acid influences neuronal migration from the ganglionic eminence to the cerebral cortex. J Neurochem 119:723-35
Kumar, Sandeep; Duester, Gregg (2010) Retinoic acid signaling in perioptic mesenchyme represses Wnt signaling via induction of Pitx2 and Dkk2. Dev Biol 340:67-74
Rosselot, Carolina; Spraggon, Lee; Chia, Ian et al. (2010) Non-cell-autonomous retinoid signaling is crucial for renal development. Development 137:283-92
Urban, Noelia; Martin-Ibanez, Raquel; Herranz, Cristina et al. (2010) Nolz1 promotes striatal neurogenesis through the regulation of retinoic acid signaling. Neural Dev 5:21
Levi, Boaz P; Yilmaz, Omer H; Duester, Gregg et al. (2009) Aldehyde dehydrogenase 1a1 is dispensable for stem cell function in the mouse hematopoietic and nervous systems. Blood 113:1670-80

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