Pearring Lab at the University of Michigan
Our laboratory studies the mechanisms underlying cellular polarity and organelle biogenesis in photoreceptors, the light-sensing cells of the vertebrate retina. Light is captured by the outer segment organelle, which is the largest primary cilium in the human body. Importantly, defects associated with ciliary formation, function and/or trafficking often result in photoreceptor dysfunction or death leading to human blindness.
We are currently pursuing two main directions.
Protein delivery to the light-sensing outer segment organelle of photoreceptors.
Understanding the underlying mechanisms that establish and maintain the subcellular distribution of proteins remains a central unsolved problem in cell biology. Photoreceptors serve as a productive model for studying this phenomenon since they are highly polarized neurons with a clearly defined function and a wealth of biological techniques developed for their study. Additionally, defects in protein trafficking and mislocalization in photoreceptors underlie many form of inherited retinal degenerative diseases. Our lab aims to understand the basic cell biological mechanisms employed by photoreceptors to ensure polarized delivery of signaling and structural proteins to the light-sensitive outer segment compartment. Current projects include:
How are proteins segregated between the outer segment membrane subdomains: the discs and ciliary plasma membrane? The light-sensing ability of photoreceptors depends on the localization of different signaling proteins to these specific subdomains. We are exploring the molecular mechanisms guiding delivery of the cyclic nucleotide gated channel to the ciliary plasma membrane and how this is similar and/or different from disc-specific protein delivery.
How are membrane proteins deposited into the light-sensing outer segment compartment of photoreceptors? We are investigating the intracellular route of membrane proteins destine to reside in the ciliary outer segment using an ex vivo live imaging approach to monitor trafficking events in realtime (see our movie below).
Biogenesis of the ciliary outer segment organelle
Most cells in the human body contain a primary cilium, a small antenna-like organelle that extends from the cell's surface and perceives extracellular signals. Interestingly, many sensory cells have adapted their primary cilium to detect a particular environmental stimulus. For vertebrate photoreceptors, the primary cilium was modified to detect light by filling it with hundreds of flattened membrane discs. Throughout the lifespan of an animal, discs undergo continuous renewal with new membranes added at the outer segment base and old membranes shed from the tip. However, the molecular mechanism of disc formation and renewal remains elusive. Current project includes:
What are the molecular programs regulating outer segment renewal? Using Next-Generation sequencing we are analyzing the transcriptome and translatome during robust outer segment biosynthesis.
How is photoreceptor outer segment biogenesis impacted during disease? Using advanced microscopy techniques we are investigating how the process of outer segment renewal is impacted during inherited retinal degenerative disease.
