They are generated and maintained by an elaborate process of vesicular protein trafficking, microtubule extension and resorption and stringently regulated activity of microtubule motor proteins. This process is called Intraflagellar Transport (IFT). Cilia are involved in regulating diverse developmental and adulthood signaling cascades, including sonic hedgehog signaling and Wnt signaling. Being nearly ubiquitous, dysfunction of cilia results in severe developmental disorders, including neurodegenerative diseases of the eye and brain.
Photoreceptors are polarized sensory neurons with a distinct inner segment (IS) and the photosensory outer segment (OS). The OS is a sensory (or primary) cilium, which contains membranous discs arranged in a coin-stack like fashion. These discs are periodically shed at the tip and are renewed at the base. Such phenomena require a high level of stringently regulated trafficking of membrane and protein components from IS to OS via a narrow bridge-like structure, called the transition zone (TZ). The unique and distinct protein composition of the ciliary OS membrane of photoreceptors is essential to maintain the polar nature of the photoreceptors. Consistently, any defects in the trafficking machinery of photoreceptors due to dysfunction of the cilia results in degeneration and blindness.
The TZ of photoreceptor cilium is implicated in regulating the sorting and trafficking of specific protein and other cargo components to the OS. We are interested in understanding the development, composition and function of the photoreceptor ciliary TZ in order to obtain mechanistic insights into the mode of regulated protein trafficking and maintenance of photoreceptor polarity. Our studies have identified three key ciliary proteins that are involved in photoreceptor ciliary protein: RPGR (retinitis pigmentosa GTPase regulator), RP2 (retinitis pigmentosa 2), and CEP290 (centrosomal protein of 290 kDa). These proteins not only modulate ciliary transport but are also mutated in various forms of human retinal degenerative diseases. Following three major projects are currently being carried out in our laboratory.