AVN Members : Dr. David Pilgrim

My lab studies how photoreceptors develop and maintain their unique morphologies, which are specifically adapted to the reception of incoming light. Tissue patterning, interactions with neighboring cells, development of cell polarity, and proper cell functioning are all important factors in the establishment and maintenance of a particular cell size and structure. We use zebrafish as a model to understand both retinal biology during development, and the cellular changes underlying human disease. In our work, we create transgenic and mutant zebrafish and study their photoreceptors in detail using immunohistochemistry, confocal imaging, and electron microscopy.

Two current projects in the lab have relevance to the visual system.

Molecuar Chaperone involvementin Lens Development.

UNC45b is a myosin-specific chaperone that, together with the general heat shock protein HSP90, is involved in myosinassembly in skeletal muscle. Using GWAS, we have found alterations in UNC45b associated with familial juvenile cataracts. This prompted us to look for gene expression outside muscle, and we showed unc45b expression in both human and zebrafisheye. We hypothesize that developmental cataracts may be caused by the necessity for UNC45b function in the homeostasis of non-muscle myosin assemby or foldingduring maturation of lens fiber cells.

An Ancient Protein Necessary for Photoreceptor Function

The Unc119 protein family was named after a mutation originally found in my lab, which regulates nervous system patterning in the nematode C. elegans. Unc119proteins are found in all metazoans examined and are both extremely highly conserved at the sequence and functional level and present at low copy (one to four gene paralogs per genome). Unc119 is enriched in retina, and in mammals isassociated with cone-rod dystrophies and retinal degeneration. We are using zebrafish to test the cellular function of each unc119 homologue, and in the role of the protein during photoreceptor development, including cellular localization and the identification of interacting proteins. We are particularly interested in testing the prevalence of Unc119 mutations in patients with ocular or visual defects, whether different classes of mutation may be associated with different phenoypes, and also on recapitulating such phenotypes in the zebrafish system.