Photoreceptors are highly specialized light-sensitive cells of the retina, essential for visual perception. The loss of photoreceptors in the human eye due to genetic causes is a frequent cause of blindness. Although a lot of effort has been devoted to the studies of the photoreceptor cell, some essential aspects of its differentiaton and function remain poorly understood. In particular, the molecular mechanisms, which lead to the assembly of the sophisticated photoreceptor morphology remain virtually unknown. Defects of these mechanisms frequently cause photoreceptor death and lead to blindness in humans. ? ? A very productive way to gain insight into the genetic causes of photoreceptor degeneration in the human eye is to study animal models of photoreceptor loss. The zebrafish is one of the leading animal models used to study the genetic causes of retinal disease. Using a mutagenesis approach in zebrafish, we have identified and characterized several mutations that lead to photoreceptor death. A mutation in the mok gene appears to affect the positioning of the photoreceptor nucleus and causes a particularly early loss of photoreceptor cells. We have characterized the molecular nature of the mok genetic defect and determined that it affects the activity of an intracellular motor complex. This complex, among other functions, is known to regulate the positioning of the cell nucleus. These studies reveal the role of molecular motors in vertebrate photoreceptor differentiation and survival. ? ? We are planning to characterize the role of the mok motor complex components in photoreceptor differentiation and survival using both the existing chemically-induced mutant alleles as well as reverse genetic antisense interference strategies. In particular, we would like to focus on the role of the mok motor in the positioning of the cell nucleus and in the subcellular localization of proteins associated with the Bardet-Biedl syndrome (BBS), a human disorder leading to the loss of photoreceptor cells, kidney defects, obesity, and polydactyly. Our preliminary studies indicate that the mok gene is necessary for the proper subcellular localization of BBS polypeptides. We will investigate the interactions of Mok and BBS proteins using in vitro biochemical approaches as well as in vivo genetic tests in the zebrafish embryo. These studies will provide insight into the mechanisms of photoreceptor degeneration and their relatedness to human photoreceptor diseases. ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY016859-01
Application #
6964149
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Mariani, Andrew P
Project Start
2005-09-15
Project End
2010-08-31
Budget Start
2005-09-15
Budget End
2006-08-31
Support Year
1
Fiscal Year
2005
Total Cost
$350,783
Indirect Cost
Name
Massachusetts Eye and Ear Infirmary
Department
Type
DUNS #
073825945
City
Boston
State
MA
Country
United States
Zip Code
02114
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
Zhao, Chengtian; Malicki, Jarema (2011) Nephrocystins and MKS proteins interact with IFT particle and facilitate transport of selected ciliary cargos. EMBO J 30:2532-44
Beyer, Jill; Zhao, Xinping C; Yee, Richard et al. (2010) The role of crumbs genes in the vertebrate cornea. Invest Ophthalmol Vis Sci 51:4549-56
Avanesov, Andrei; Malicki, Jarema (2010) Analysis of the retina in the zebrafish model. Methods Cell Biol 100:153-204
Kennedy, Breandán; Malicki, Jarema (2009) What drives cell morphogenesis: a look inside the vertebrate photoreceptor. Dev Dyn 238:2115-38
Jing, Xiaotang; Malicki, Jarema (2009) Zebrafish ale oko, an essential determinant of sensory neuron survival and the polarity of retinal radial glia, encodes the p50 subunit of dynactin. Development 136:2955-64
Kitambi, Satish S; McCulloch, Kyle J; Peterson, Randall T et al. (2009) Small molecule screen for compounds that affect vascular development in the zebrafish retina. Mech Dev 126:464-77
Kitambi, Satish S; Malicki, Jarema J (2008) Spatiotemporal features of neurogenesis in the retina of medaka, Oryzias latipes. Dev Dyn 237:3870-81

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