Professor of Ophthalmology & Visual Sciences and
Adjunct Professor of Neurobiology & Anatomy and of Biology
Diploma University of Heidelberg, Germany
Ph.D. University of Heidelberg, Germany
Wolfgang Baehr's Lab Page
Wolfgang Baehr's PubMed Literature Search
Rod and cone photoreceptors have evolved into highly polarized structures consisting of three distinct areas: the outer segment containing membrane disks housing proteins involved in phototransduction, the inner segment where biosynthesis occurs, and the synaptic terminal that transmits excitation by light to downstream neurons. The inner segment (cell body) connects to an outer segment through a narrow 9+0 cilium, and to the synaptic terminal by a slender axon. Outer segments of rods and cones are renewed roughly every ten days. New disks are made at the proximal end, old disks are shed at the distal end, and phagocytosed by the adjacent retinal pigment epithelium (RPE). Daily renewal of ~10% (about 100 disks) of the outer segment membrane requires a high rate of biosynthesis to replace OS proteins, with reliable transport and targeting pathways.
My laboratory explores mechanisms in membrane protein transport in mammalian rod and cone photoreceptors, specifically post-biosynthesis transport of integral membrane and peripheral membrane-associated proteins to the outer segments. Integral membrane proteins are synthesized at ER-associated ribosomes and exported to the Golgi apparatus. Peripheral membrane proteins are synthesized in the cytosol and become ER-associated if prenylated or acylated. Vesicles emerge from the trans-Golgi network (TGN) and transport to the base of the cilium where they fuse with the cell membrane. Finally, cargo is assembled for intraflagellar transport to the outer segment where phototransduction occurs.
We are interested in proteins/genes mediating transport, particularly molecular motors (kinesin-II), small GTP binding proteins (rab8, rab11), prenyl binding proteins mediating transport of prenylated proteins (PrBP/delta or PDE6D), acyl binding proteins (UNC119) involved in transport of G protein subunits, and centrins, small Ca2+ binding proteins involved in ciliogenesis. We produce knockouts/knockins, transgenics to monitor the consequences of gene knockouts, dominant negative transgenes, or short hairpin RNAi. Most frequently applied techniques are standard biochemistry/molecular biology, confocal and electron microscopy, electroretinography (photoreceptor function), optomotry (behaviour), in-vivo electroporation (transfer of genes into neonatal retina), and gene therapy (AAV virus).
Trafficking of lipidated proteins (PDE6, GRK1, GNAT1) in Photoreceptor (Zhang et al., 2015). Lipidated proteins are extracted from the ER, and delivered by a lipid-binding protein (Λ). A key event is interaction with the Cargo Dislocation Factor ARL3-GTP which delivers cargo to the destination membrane Zhang et al., 2015).
- Zhang H, Constantine R, Vorobiev S, Chen Y, Seetharaman J, Huang YJ, Xiao R, Montelione GT, Gerstner CD, Davis MW, Inana G, Whitby FG, Jorgensen EM, Hill CP, Tong L, Baehr W. UNC119 is required for G protein trafficking in sensory neurons. Nat Neurosci. 2011 Jun 5;14(7):874-80. PMCID: PMC3178889.
- Jiang L, Wei Y, Ronquillo CC, Marc RE, Yoder BK, Frederick JM, Baehr W. Heterotrimeric Kinesin-2 (KIF3) Mediates Transition Zone and Axoneme Formation of Mouse Photoreceptors. J Biol Chem. 2015 15;290(20):12765-78. PMCID: PMC4432293
- Baehr W. Membrane protein transport in photoreceptors: the function of PDEδ: the Proctor lecture. Invest Ophthalmol Vis Sci. 2014 Dec 30;55(12):8653-66. PMID: 25550383.
- Zhang H, Hanke-Gogokhia C, Jiang L, Li X, Wang P, Gerstner CD, Frederick JM, Yang Z, Baehr W. Mistrafficking of prenylated proteins causes retinitis pigmentosa 2. FASEB J. 2015 Mar;29(3):932-42. PMCID: PMC4422365.
- Ying G, Avasthi P, Irwin M, Gerstner CD, Frederick JM, Lucero MT, Baehr W. Centrin 2 is required for mouse olfactory ciliary trafficking and development of ependymal cilia planar polarity. J Neurosci. 2014 Apr 30;34(18):6377-88. PMCID: PMC4004820.
- Avasthi P, Scheel JF, Ying G, Frederick JM, Baehr W, Wolfrum U. Germline deletion of Cetn1 causes infertility in male mice. J Cell Sci. 2013 Jul 15; 23641067. PMCID: PMC3711207.