Jennifer Hocking

Photoreceptors, the primary sensory cells of the eye, have highly specialized morphologies optimized for the detection of light. In fact, the rod and cone photoreceptors, responsible for low-light vision and high-acuity colour vision respectively, are named based on the shapes of their sensory endings, the so-called outer segments. Outer segments contain stacks of membranous disks laden with the opsin photopigments. Amazingly, the large outer segments must not only be built during development, but must be actively maintained through constant shedding of old disks and synthesis of new disks. In humans, photoreceptors cannot be regenerated, and any process that leads to destabilization of the outer segment will cause cell death and reduced visual acuity.

Our lab studies the mechanisms underlying formation of an outer segment during development and its ongoing maintenance in the adult, with the goal of expanding out understanding of the cell biology underlying retinal dystrophies. We use zebrafish as an animal model because zebrafish are vision-dependent predators with large eyes and excellent vision. Their retinas have an abundance of both rods and cones, allowing us to study both cell types. Further, we have many tools for manipulating zebrafish genetics and uncovering the genes necessary for outer segments.

In one project, we are looking at the role of the actin cytoskeleton in outer segment stabilization and renewal. Actin does not form the architecture of the outer segment but it is proposed to play three roles: 1) stabilization of microvilli-like calyceal processes that surround the base of outer segment, but are of unknown function; 2) facilitating transport of proteins into the outer segment; and 3) promoting expansion of nascent disks. None of these roles is well understood, but each may be fundamental to maintaining intact outer segments.

In a second project, we are examining how neural activity influences cell morphology. Photoreceptors are neurons that conduct ionic current, but oddly the current flow is highest in the dark and restricted in the light. Protein transport into the outer segment is influenced by the light:dark cycle, and we propose that formation of outer segment disks is affected by the ability of the cell to respond to light. We are currently modeling in zebrafish the human disease Cone Rod Dystrophy with Supernormal Rod Response (CDSR), which is caused by mutations in the potassium channel gene KCNV2. We predict that the human phenotype results from alterations to both photoreceptor current flow and morphology.