There is a fundamental gap in understanding how stochastic cell fate determination regulates the formation of the retinal mosaic. Continued existence of this gap represents an important problem in retinal development because, until it is filled, the understanding of normal and pathological eye development will remain fragmented and incomplete; The long-term goal is to understand how different classes of photoreceptors are specified by stochastic mechanisms that are intrinsic to an individual photoreceptor. The objective in this particular application is to identify additional genes involved in regulating the stochastic determination of R7 photoreceptor cell fate in an effort to develop a coherent gene network that integrates the function of spineless and tango into a comprehensive testable model. The central hypothesis is that a complex gene network controls the specification of Rh3 and Rh4 expressing R7 photoreceptor cells that includes spineless, tango, as well as additional unidentified genes. This hypothesis has been formed based on preliminary data produced in the applicant's laboratory. The rationale for the proposed research is the observation that the proportion of R7 photoreceptors that express one visual pigment or another is a continuously variable quantitative trait. This suggests that the genes within this network, which produces these different photoreceptor cell types, can be identified and characterized using quantitative genetic approaches. Guided by this strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Identify Quantitative Trait Loci that regulate R7 photoreceptor cell fate and opsin expression; and 2) Develop and test a gene network model based on these Quantitative Trait Loci. Under the first aim, a proven quantitative genetics approach will be applied to examine the specification of Rh3 and Rh4 expressing R7 photoreceptor cells. Under the second aim, the identified genes will be assembled into a network model and tested for their ability to regulate R7 photoreceptor cell subtype specification. The approach is innovative, because it uses new technologies to examine the mechanics of retinal development in a way that has not been previously undertaken and because this approach is likely to provide a type of information that promises to fundamentally alter our understanding of eye and retina development. The proposed research is significant, because it is expected to vertically advance and expand the understanding of how the retina is formed and develops. Ultimately, such knowledge has the potential to impact the understanding and treatment of congenital eye defects and malformations and influence the development of new treatments for visual system diseases through the manipulation of specific cells within the retina.
The proposed research is relevant to public health because the discovery of mechanisms that regulate cell fate determination in the developing retina is ultimately expected to increase our understanding of the pathogenesis of developmental abnormalities of the eye in humans as well as the potential mechanisms that may be used to manipulate specific cells of the eye in human visual disorders. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help reduce the burdens of human disability.
