Collaborative Research: Uncovering Principles Underlying Rod Photoreceptor Outer Segment Renewal and Size

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Photoreceptors are neuronal cells that form before and soon after birth, and cannot be replaced if they degenerate. The light-sensing antenna of photoreceptor cells is an essential feature of the cells and must be continuously refreshed (or regenerated) in order to optimally capture light. Without this antenna, photoreceptor cells cannot sense light, and the photoreceptor cells die, resulting in blindness. This continuous regeneration occurs by the addition of newly produced proteins and membranes at its base and by the shedding of the oldest proteins and membranes from its tip. Remarkably, the photoreceptor cell is capable of keeping its antenna at a constant length, as the dynamic processes of growth and shedding occur. The goal of this project is to discover the rules used by photoreceptor cells in the eye to determine the length of their antenna. In addition to understanding this vital regeneration process, this proposal will allow a new generation of STEM scholars to learn the skills that are vital to thrive in STEM disciplines. In particular, a cohort of students, undergraduates and graduate students, will participate in the research and gain vital training and mentoring in mathematical/computer modeling and life science. This project also incorporates activities to increase current and future participation of underrepresented groups in STEM education and careers.This project seeks to discover the rules used by photoreceptor cells to calculate and balance rates of growth and shedding of proteins and membranes in their light-sensing antenna to maintain a constant length of their cellular antennas. Rules will be discovered using genetically manipulated zebrafish that reveal the dynamic regenerative process in the photoreceptor's antenna. One set of experiments is designed to stimulate extra growth at the base, and results will reveal whether antenna length increases or whether shedding increases to balance the extra growth rate to maintain a length constant. Another set of experiments is designed in which shedding from the tip will be blocked, and results will reveal whether antenna length will increase due to blocked shedding or whether growth at the base slows to balance the extra length at the tip to maintain a length constant. Finally, mathematical models will be developed to predict the length of photoreceptor antenna following experimental manipulation. Such models are based on our current understanding of growth and shedding, where model output will be fit/compared to experimental data of antenna length. The beauty of such a model is that it can be used to help reveal (and even predict, alongside with future experiments) the regulatory mechanisms that photoreceptors use to maintain the constant length of their sensory antennas. The outcomes of this proposal will serve as an important foundation for future efforts to define the cellular machinery in photoreceptors that contribute to the critical regenerative process of their light-sensing antenna.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.