CILIA IN EYE DEVELOPMENT AND DISEASE

Massachusetts Eye And Ear Infirmary, Boston MA

Investigators

Linked publications & trials

Abstract

[unreadable] DESCRIPTION (provided by applicant): Cilia play an essential role in many developmental processes. In the context of the nervous system, cilia are a key structural component of sensory neurons in both vertebrates and invertebrates. In the vertebrate visual system, the photosensitive component of the cell, known as the outer segment, connects to the rest of the cell body via a narrow constriction that tightly surrounds a ciliary axoneme, and is referred to as the connecting cilium. In the absence of this cilium, the photoreceptor outer segment does not form. [unreadable] [unreadable] A growing body of evidence indicates that ciliary defects cause Bardet-Biedl Syndrome (BBS), a group of human disorders that involve photoreceptor loss and consequently blindness. The clinical manifestations of BBS also involve polydactyly, obesity, kidney disease, anosmia, and mental retardation. To understand the role of cilia in photoreceptor differentiation and disease, we are planning to take both forward and reverse genetic approaches. In a large-scale genetic screen, we identified mutations in the elipsa gene that lead to early loss of cilia, the absence of outer segment formation, and subsequently photoreceptor cell death and blindness. We propose to apply molecular and genetic approaches to study the role of elipsa in photoreceptor differentiation and survival. [unreadable] [unreadable] To carry out its function, Elipsa most likely interacts with other proteins. To determine their identity, we used a molecular genetic approach known as the yeast two-hybrid screen. This effort led to the isolation of several factors, one of which is known to function as an effector of an enzyme family that regulates the trafficking of intracellular vesicles. We are planning to capitalize on this finding to study the intracellular trafficking in the photoreceptor cell - a process known to be of paramount importance of photoreceptor function and survival. [unreadable] [unreadable] In parallel to these efforts, we will apply a complementary reverse genetic approach to study ciliogenesis. Using this approach, known as TILLING, we will generate zebrafish mutants of selected BBS genes. The mutant strains will allow us to study in the detail the role of BBS genes in cilia formation and maintenance, as well as their relationship to other genetic pathways involved in ciliogenesis. The results of these studies will enhance our ability to produce treatment for photoreceptor loss in photoreceptor disorders. [unreadable] [unreadable] [unreadable]