Our research is focused on the biology of cilia, cellular organelles with unique evolutionary fate and physiological role. Cilia are most commonly associated with cellular motility, propagating the movement of unicellular organisms and animal spermatozoa. However, most cell types in the human body express these organelles, where they serve as chemical and mechanical sensors. Dramatic examples of specialized cilia are found in the rod and cone cells in the eye where they house the entire photoreceptor signal transduction machinery. Given their central role in so many physiological processes, it is not surprising that their malformation or dysfunction can lead to a variety of disorders, such as: sterility, blindness, lung dysfunction, situs inversus polycystic kidney disease and has been recently implicated in obesity and mental retardation.
In spite of the importance of cilia in many biological systems, the mechanism(s) and the inventory of proteins required for cilium formation are poorly understood. Our goal is to understand the molecular underpinnings of cilia biology, including their formation, pruning and regeneration. To this aim we are developing novel approaches and tools that will elucidate the roles of the central players in these processes as well as their orchestration into one functional unit.
To identify the repertoire of specialized proteins needed for the formation and function of cilia, we developed a novel “in silico” subtractive screen. This screen led to the identification of a large diverse group of ciliary genes, many of which, we have shown to be expressed only in ciliated cells and are required for cilia formation. Using Drosophila as a model system we are studying the role of these genes, employing a multifaceted approach including: genetics, physiology, biochemistry, imaging and bioinformatics.
We are particularly interested in the role of a family of six ciliary proteins collectively referred to as OSEGs, which are structurally related to prototypical transport proteins. They are found only in organisms with cilia, and are expressed exclusively in ciliated cells. We have shown that OSEGs play a critical role in transporting the sensory machinery from the base of the cilium into its distal part. In addition we identified two other proteins through the in silico bioinformatics screen, that are related to small GTPase proteins that regulate other cellular transport events. Our results are starting to delineate a common foundation for the organization of intracellular transport systems, which: mediate internalization of surface proteins, transferring cargo between organelles, or delivery of components from the cell body to distal ciliary compartments.
Centrioles, basal bodies and the Cilia skeleton, termed the axoneme, share a unique nine-fold symmetry that accentuates their common origin. To study how this symmetry is formed we have identified three genes that are required specifically for centriole, basal body and cilium formation in Drosophila. One of these genes has an ortholog in humans that plays a critical role in a brain developmental disease and our results indicate that the protein encoded by this gene is involved in the early steps of centriole formation.
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References:
- Avidor-Reiss T, Maer AM, Koundakjian E, Polyanovsky A, Keil T, Subramaniam S, Zuker CS (2004). Decoding cilia function: defining specialized genes required for compartmentalized cilia biogenesis. Cell, 117, 527-39
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