Funding outcome

Usher syndrome is the most common form of inherited combined vision and hearing loss, with Type I being the earliest onset and most severe. While the hearing loss is well understood, the cause of vision problems is not. The light sensitive cells at the back of the eye are the rod and cone photoreceptors, which mediate dim light and color vision, respectively. Photoreceptors cannot regenerate and must last a lifetime for vision to be maintained. Unfortunately, it is the photoreceptors that degenerate in Usher patients; however, we do not yet understand the ocular functions for the proteins produced by the six identified USH1 genes or why their loss leads to photoreceptor death. In the Hocking lab, we are developing zebrafish as a model for studying Usher syndrome Type I. Zebrafish is widely used for eye disease research because the anatomy, genetics and development of the eye are highly comparable to humans. In this project, we focus the most recent USH1 gene, espin (ESPN/USH1M). Photoreceptors detect light through a large sensory ending, the outer segment, which extends from an apical region of the cell known as the inner segment. Also extending from the inner segment is a ring of finger-like projections termed the calyceal processes (CPs) that surround the base of the outer segment like a ring of ramparts. USH1 proteins were recently found to localize CPs, but the function of CPs in supporting vision and the role of USH1 proteins in CPs remain unknown. Here, we study the dynamics of CPs and the consequences of either a reduction or increase in espin on CPs, the outer segment, and the photoreceptor. Analysis will be done through confocal and electron microscopy to examine changes at the tissue, cellular and subcellular level. Further, testing of the fish visual function will be tested by electroretinogram. This work will provide a new basis for understanding USH1 retinal disease and developing appropriate targeted treatments.