Professor of Ophthalmology & Visual Science
Adjunct Professor of Neurobiology and Anatomy
Adjunct Professor of Biology
The Baehr Lab
Neurobiology of Disease
Model of light induced transpocation of transducin in rod photoreceptors. In light, as part of a desensitization mechanism, transducin migrates to the inner segment. In dark, it slowly returns. Mechanisms of translocation are controversial, and tought to be based on diffusion, vesicular transport, or a combinantion of both.
Phototransduction, the retinoid cycle, membrane protein transport in photoreceptors and mouse models for inherited retinal disease
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 molecular biology, confocal and electron microscopy, optomotry (behaviour), in-vivo electroporation, and gene therapy (AAV virus).
Selected Publications (of over 160):
Karan, S., Frederick, J.M., and Baehr, W. (2010) Novel functions of photoreceptor guanylate cyclases revealed by targeted deletion. Mol Cell Biochem, 334:141-155. PMCID: PMC2832916
Avasthi, P., Watt, C.B., Williams, D.S., Le, Y.Z., Li, S., Chen, C.K., Marc, R.E., Frederick, J.M., and Baehr, W. (2009) Trafficking of membrane proteins to cone but not rod outer segments is dependent on heterotrimeric kinesin-II. J. Neurosci., 29(45):14287-14298. PMCID: 2788486
Zhang, H., Fan, J., Li, S., Karan, S., Rohrer, B., Palczewski, K., Frederick, J.M., Crouch, R.K., and Baehr, W. (2008) Trafficking of Membrane-associated Proteins to Cone Photoreceptor Outer Segments Requires 11-cis-Retinal. J Neurosci, 2(15):4008-4015.
Karan, S., Zhang, H., Li, S., Frederick, J.M., and Baehr, W. (2008) A model for transport of membrane-associated phototransduction polypeptides in rod and cone photoreceptor inner segments. Vision Res, 48:442-452.
Zhang, H., Li, S., Detwiler, P., Rieke, F., Frederick, J., and Baehr, W. (2007) Deletion of PrBP/δ impedes transport of GRK1 and PDE to photoreceptor outer segments. PNAS, 104(21):8857-8862.
Baehr, W., Karan, S., Maeda, T., Luo, D.G., Li, S., Bronson, J.D., Watt, C.B., Yau, K.W., Frederick, J.M., and Palczewski, K. (2007) The function of Guanylate Cyclase 1 (GC1) and Guanylate Cyclase 2 (GC2) in rod and cone photoreceptors. J. Biol. Chem., 282:8837-8847.