Faculty

DAVID S. WILLIAMS

Adjunct Professor of Pharmacology and Neurosciences

TEL: 858-546-9439

FAX: 858-546-9389

email: dswilliams@ucsd.edu

Ph.D., Australian National University

Key Words: Photoreceptor cells; Cytoskeleton; Myosin; Kinesin; Rhodopsin; Usher syndrome; Signal transduction

The overall goal of ourlab is to learn about photoreceptor cells in the retina. These cells whose function is to capture light efficiently and transduce it into a neural signal are the epitome of a specialized cell.

A major theme of our studies has been the investigation of cellular and molecular mechanisms involved in the turnover of phototransductive proteins. This process is a major undertaking for photoreceptor cells. Each human eye synthesizes de novo some 10 billion opsin molecules per second. The opsin molecules and other phototransductive proteins must be transported from their site of synthesis in the proximal inner segment, through the inner segment, and along a cilium to the outer segment. At the base of the outer segment, membrane proteins become incorporated into new disks. Defects at any stage may result in photoreceptor cell death, and thus blindness.

Our studies concern motor proteins that are involved in this turnover. Two such proteins are myosin VIIa (an actin motor) and KIF3a, a component of kinesin II (a microtubule motor). Mutations in the myosin VIIa gene cause Usher syndrome 1B, a major form of inherited blindness combined with deafness, resulting from photoreceptor cell degeneration and defects in cochlear hair cell development. Using the Cre-lox system to knock out KIF3a selectively in photoreceptor cells, we found that kinesin II is also essential for photoreceptor cell viability. Our studies combine in vitro and in vivo approaches to help us understand the cell biology and biochemistry of how these motors work.

We are also interested in the other Usher 1 proteins, which include two cadherins and a PDZ domain protein, as well as gene therapy experiments, aimed at correcting the retinal dysfunction caused by the different forms of Usher syndrome type 1.

For further information, please connect to our lab web site: http://medicine.ucsd.edu/williams/index.html

Selected Publications:

Liu X, Ondek B, Williams DS: Mutant myosin VIIa causes defective melanosome distribution in the RPE of shaker-1 mice. Nature Genetics 19:117-118, 1998.

Liu X, Udovichenko, IP, Brown SDM, Steel KP, Williams DS: Myosin VIIa participates in opsin transport through the photoreceptor cilium. Journal of Neuroscience 19:6267-6274, 1999.

Marszalek JR, Liu X, Roberts E, Chui D, Marth J, Williams DS, Goldstein LSB: Genetic evidence for a kinesin-II mediated pathway for opsin and arrestin transport in mammalian photoreceptors. Cell 102:175-187, 2000.
 

Udovichenko IP, Gibbs D, Williams DS: Actin-based motor properties of native myosin VIIa. Journal of Cell Science, 115:445-450, 2002.
 

Gibbs D, Kitamoto J, Williams DS: Abnormal phagocytosis by retinal pigmented epithelium that lacks myosin VIIa, the Usher syndrome 1B protein. Proceedings of the National Academy Sciences, 100:6481-6486, 2003.