Most cells in the body contain a primary cilium, a microtubule-based structure that is important for sensing the environment around the cell and initiating signals so that the cell can respond. Retinal photoreceptor cells possess a unique adaptation of the cilium. The outer segment of photoreceptors is a highly specialized cilium consisting of stacks of membranous discs that contain the components required to convert photons of light into changes in membrane potential. Disruption of this structure invariably causes blindness. A group of diseases termed ciliopathies are caused by mutations in genes that are central to development and maintenance of cilia, and retinal degeneration is commonly a component of these diseases. Therefore, understanding how the cilium is built and maintained is of significant importance. In general, our knowledge of transcriptional regulatory networks that control expression of ciliary genes is lacking. Given that microRNAs are emerging as important and ubiquitous components of gene regulatory networks, we propose that miRNAs play an important role in photoreceptor outer segment development. We have observed that knockdown of miR-129-3p expression in zebrafish disrupts outer segment development, and the experiments described here seek to uncover the relationships between miR-129-3p, its targets, and the cilium. The zebrafish is the optimal model to test these relationships given its well-characterized developmental program, accessibility to imaging at all developmental stages, and its genetic malleability. These experiments will illuminate a functional role of miR-129-3p for photoreceptor outer segment development while also having important implications for other ciliated cells. These experiments will broaden our understanding of gene regulation networks in the context of ciliogenesis, and have the potential to identify novel genes required for this fundamental cellular process.
Recent evidence suggests miRNAs comprise an important yet poorly understood part of retinal biology. It has been shown that disruption of miRNA expression can lead to defects in ciliogenesis. We have begun to extend that work into the retina and have found that miR-129-3p is important for outer segment development. Deciphering the role of this miRNA and others in the photoreceptor will enhance our understanding of retinal degenerative diseases, and could serve as a basis for gene-therapy strategies to treat them.
| Lessieur, Emma M; Fogerty, Joseph; Gaivin, Robert J et al. (2017) The Ciliopathy Gene ahi1 Is Required for Zebrafish Cone Photoreceptor Outer Segment Morphogenesis and Survival. Invest Ophthalmol Vis Sci 58:448-460 |
