We have identified a blind zebrafish mutant with rapid degeneration of cone photoreceptors due to a mutation in the cone phosphodiesterase c (pde6c) gene, a key regulatory component in cone phototransduction. We will use this mutant combined with the advantages of the zebrafish model system to answer two fundamental questions in photoreceptor biology. 1. What are the cell-type and cell density requirements that lead to the death of healthy photoreceptors in the presence of dying photoreceptors (the """"""""bystander effect"""""""")? 2. What is the molecular pathway leading to cone degeneration in the absence of phosphodiesterase? Zebrafish is a vertebrate model system that provides several advantages for studying retinal degeneration. In this case, the loss of PDE6c in zebrafish provides a unique opportunity to gather new information about retinal degeneration. Our current understanding of the causes of photoreceptor degeneration is not sufficient to develop successful therapies. Zebrafish develop rapidly and have a well-characterized retina. Furthermore, they are optically clear, can be used efficiently in genetic screens and, importantly, can be made mosaic easily through cell transplantation. These features will enable us to go beyond studies begun in other systems. New information from the zebrafish model will enhance our understanding of retinal degeneration and aid in the development of therapies. We plan to take advantage of our detailed understanding of the photoreceptor's phototransduction cascade and the genetic and molecular tools unique to zebrafish to determine the molecular trigger(s) stimulating (Aim #2) and preventing (Aim #3) degeneration. We also will use our cone degeneration mutant to make mosaic retinas containing mixtures of mutant and non-mutant cones to dissect parameters essential for causing the bystander effect (Aim #1).
Zebrafish is a vertebrate model system that provides several advantages for studying retinal degeneration. We have identified a blind zebrafish mutant with rapid degeneration of cone photoreceptors due to a mutation in the cone phosphodiesterase c gene (pde6c), a key regulatory component in cone phototransduction. New information from the study of the zebrafish mutant pde6cw59 will enhance our understanding of retinal degeneration and aid in the development of therapies to treat this common inherited form of blindness.
|Lewis, Alaron A; Mahoney, Joseph T; Wilson, Neil et al. (2015) Identification of amacrine subtypes that express the atypical cadherin celsr3. Exp Eye Res 130:51-7|
|Decker, Amanda R; McNeill, Matthew S; Lambert, Aaron M et al. (2014) Abnormal differentiation of dopaminergic neurons in zebrafish trpm7 mutant larvae impairs development of the motor pattern. Dev Biol 386:428-39|
|Ma, E Y; Lewis, A; Barabas, P et al. (2013) Loss of Pde6 reduces cell body Ca(2+) transients within photoreceptors. Cell Death Dis 4:e797|
|Lewis, Alaron; Wilson, Neil; Stearns, George et al. (2011) Celsr3 is required for normal development of GABA circuits in the inner retina. PLoS Genet 7:e1002239|
|Brockerhoff, Susan E; Fadool, James M (2011) Genetics of photoreceptor degeneration and regeneration in zebrafish. Cell Mol Life Sci 68:651-9|
|Brockerhoff, Susan E (2011) Phosphoinositides and photoreceptors. Mol Neurobiol 44:420-5|
|Bachmann-Gagescu, Ruxandra; Phelps, Ian G; Stearns, George et al. (2011) The ciliopathy gene cc2d2a controls zebrafish photoreceptor outer segment development through a role in Rab8-dependent vesicle trafficking. Hum Mol Genet 20:4041-55|
|Lewis, Alaron; Williams, Philip; Lawrence, Owen et al. (2010) Wild-type cone photoreceptors persist despite neighboring mutant cone degeneration. J Neurosci 30:382-9|