GENETIC ANALYSIS OF PHOTORECEPTOR DIFFERENTIATION

描述（申请人提供）：光感受器是视网膜上高度特化的光敏细胞，对视觉感知至关重要。由于遗传原因，人眼中光感受器的丧失是导致失明的常见原因。尽管对光感受器细胞的研究已经投入了大量的精力，但对其分化和功能的一些基本方面仍然知之甚少。特别是，导致复杂的光感受器形态组装的分子机制仍然几乎未知。这些机制的缺陷经常导致光感受器死亡并导致人类失明。

DESCRIPTION (provided by applicant): 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.