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. 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. 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. 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.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Mariani, Andrew P
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Tufts University
Schools of Dentistry
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Hazime, Khodor; Malicki, Jarema J (2017) Apico-basal Polarity Determinants Encoded by crumbs Genes Affect Ciliary Shaft Protein Composition, IFT Movement Dynamics, and Cilia Length. Genetics 207:1041-1051
Malicki, Jarema J; Johnson, Colin A (2017) The Cilium: Cellular Antenna and Central Processing Unit. Trends Cell Biol 27:126-140
Pooranachandran, Niedharsan; Malicki, Jarema J (2016) Unexpected Roles for Ciliary Kinesins and Intraflagellar Transport Proteins. Genetics 203:771-85
Boubakri, Meriam; Chaya, Taro; Hirata, Hiromi et al. (2016) Loss of ift122, a Retrograde Intraflagellar Transport (IFT) Complex Component, Leads to Slow, Progressive Photoreceptor Degeneration Due to Inefficient Opsin Transport. J Biol Chem 291:24465-24474
Leventea, E; Hazime, K; Zhao, C et al. (2016) Analysis of cilia structure and function in zebrafish. Methods Cell Biol 133:179-227
Malicki, Jarema; Avidor-Reiss, Tomer (2014) From the cytoplasm into the cilium: bon voyage. Organogenesis 10:138-57
Malicki, Jarema (2012) Who drives the ciliary highway? Bioarchitecture 2:111-7
Zhao, Chengtian; Omori, Yoshihiro; Brodowska, Katarzyna et al. (2012) Kinesin-2 family in vertebrate ciliogenesis. Proc Natl Acad Sci U S A 109:2388-93
Malicki, Jarema; Besharse, Joseph C (2012) Kinesin-2 family motors in the unusual photoreceptor cilium. Vision Res 75:33-6
Malicki, Jarema; Avanesov, Andrei; Li, Jade et al. (2011) Analysis of cilia structure and function in zebrafish. Methods Cell Biol 101:39-74

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