Wolfgang Baehr
Professor of Ophthalmology and of Neurobiology & Anatomy and of Biology
Diploma University of Heidelberg, Germany
Ph.D. University of Heidelberg, Germany
Research
My laboratory explores genes expressed in mammalian retinal pigment epithelium (RPE) and photoreceptors, particularly genes involved in phototransduction, disk morphogenesis, and the retinoid cycle. We are interested in gene defects that cause blindness, and strive to understand mechanisms that lead to retina degenerations. The most prevalent diseases in humans caused by RPE and photoreceptor gene defects are retinitis pigmentosa, Leber congenital amaurosis, and macular degeneration, each consisting of many subtypes. Within the last 15 years, over 180 disease genes have been mapped and over 120 identified.
Vision begins in the outer segments of rod and cone photoreceptor cells of the retina. Visual pigment molecules in these cells absorb photons, become activated and initiate the phototransduction cascade. The purpose of the cascade is to amplify the signal of light (the energy of a photon) and to generate an electrical impulse to be sent to the brain. About 40 individual genes are known to be involved in phototransduction or its regulation.
The phototransduction cascade. R, rhodopsin; G, G protein; E, target enzyme; CNG, cation channel; NCKX, exchanger
To study the consequence of gene mutations, we produce transgenic animal models that mimic an autosomal dominant dystrophy, or we delete a gene to generate a recessive disease model. Phototransduction genes presently under investigation are PDE6D (encoding a prenyl binding protein involved in transport and targeting), guanylate cyclases 1 and 2 (synthesizing cyclic GMP, the internal transmitter of phototransduction), and Ca2+ binding proteins termed GCAPs. An example is autosomal dominant cone dystrophy based on mutations in the GCAP1 gene. Cone photoreceptors (see figure) are responsible for color vision and visual acuity.
The purpose of the retinoid cycle is to recycle retinal, the chromophore of the light receptor rhodopsin. Key retinoid cycle genes under investigation are retinol dehydrogenases (RDH8 and RDH12) which reduce retinal to retinol (vitamin A).
Cone photoreceptors in the bovine retina. A confocal micrograph in which cone cells are labeled with an anti-arrestin antibody.
References
1. Zhang H, et al. (2007) Deletion of PrBP/δ impedes transport of GRK1) and PDE to photoreceptor outer segments. Proceedings of the National Academy of Sciences USA, In Press
2. Baehr W et al. (2007) The function of Guanylate Cyclase 1 (GC1) and Guanylate Cyclase 2 (GC2) in rod and cone photoreceptors. J. Biol. Chem. 282:8837-8847
3. Maeda A, et al. (2005) Role of photoreceptor-specific retinol dehydrogenase (prRDH) in the retinoid cycle in vivo. J. Biol. Chem. 280:18822-32
4. Sokal I, et al. (2005) A Novel GCAP1 Missense Mutation (L151F) in a Large Family with Autosomal Dominant Cone-Rod Dystrophy (adCORD). Invest. Ophthalmol. & Visual Science 46:1124-32
5. Jiang L, et al. (2005) Autosomal Dominant Cone Dystrophy Caused by a Novel Mutation in the GCAP1 gene (GUCA1A). Mol. Vis. 11:143-151
6. Nishiguchi KN, et al. (2004) A novel (I143NT) mutation in Guanylate Cyclase-Activating Protein 1 (GCAP1) associated with autosomal dominant cone dystrophy. Invest. Ophthalmol. & Visual Science 45:3863-70
7. Zhang H, et al. (2004) Photoreceptor cGMP Phosphodiesterase d-Subunit (PDEd) Functions as a Prenyl Binding Protein. J. Biol. Chem. 279:407-13
8. Zhang H, et al. (2003) Identification and Light-dependent Translocation of a Cone-specific Antigen (Cone Arrestin) Recognized by Monoclonal Antibody 7G6. Invest. Ophthalmol. & Visual Science, 44:2858-2867
