The vertebrate retina is a highly specialized sensory tissue in which complex neural circuits function to detect, interpret, and relay visual information to the brain. In many organisms, multipotent retinal progenitor cells are positionally specified to generate asymmetric patterns of photoreceptors across the surface of the initially undifferentiated neuroretinal sheet. One consequence of this patterning is the generation of a central rod-free spot that corresponds to the fovea (macula) in primates, and the area centralis in birds, which are responsible for high acuity color vision. Because the human fovea is highly susceptible to degenerative diseases, including Age-Related Macular Degeneration, there is direct clinical relevance to understanding how the fovea arises during development. However, molecular mechanisms that direct regional distribution of photoreceptors and generate the rod-free zone (RFZ) are unknown. Although few definitive markers of early area centralis progenitors have been identified, ablation experiments in the chicken embryo suggest that positional identities of retinal progenitors are set at the optic vesicle stage, prior to neurogenesis. Several transcription factors expressed asymmetrically across the dorsal-ventral (D-V) and anterior-posterior (A-P) axes of the early chick retina function in regional patterning o the retina and are required for proper retinotectal mapping. Determining the function of these genes during retinal patterning can provide a starting point for understanding how central progenitors are designated to form the RFZ. In order to test the hypotheses that area centalis progenitors are a molecularly distinct population and their positional identity is regulated by transcription factors asymmetrically expressed in dorsal-ventral and anterior-posterior domains of the retina I propose the following aims:
Specific Aim 1 : Identify genes specifically expressed in the chick area centralis to test the hypothesis that retinal progenitors that give rise to the RZ are molecularly distinct.
Specific Aim 2 : Determine if A-P, D-V and RFZ gene expression patterns are shared across phylogeny.
Specific Aim 3 : Determine if reciprocal inhibitory interactions between patterned transcription factors are sufficient to establish the RFZ. Experiments proposed here take advantage of genetic and in ovo manipulations to determine the molecular identity of RFZ progenitors and identify the function of regional transcription factors during establishment of the area centralis. The successful completion of these aims will bring novel insights to mechanisms of photoreceptor pattern formation, which are currently almost completely unknown. Further, an understanding of the macular area may provide insights into the high degree of vulnerability of this structure during aging in humans.

Public Health Relevance

The fovea, a specialized structure within the central retina that contains only cone photoreceptors, is responsible for high acuity color vision and is susceptible to degenerative diseases including Age-Related Macular Degeneration. The developmental patterning mechanisms that generate the fovea in the center of the retina are completely unknown, and this proposal will focus on uncovering the molecular pathways that function in the establishment and patterning of the central retina. The successful completion of these aims will bring novel insights to mechanisms of photoreceptor pattern formation and can be directly applied to efforts to facilitate stem cell-based therapies to regenerate cone photoreceptors within the diseased human fovea.

National Institute of Health (NIH)
National Eye Institute (NEI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Agarwal, Neeraj
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Harvard Medical School
Schools of Medicine
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Beier, Kevin T; Mundell, Nathan A; Pan, Y Albert et al. (2016) Anterograde or Retrograde Transsynaptic Circuit Tracing in Vertebrates with Vesicular Stomatitis Virus Vectors. Curr Protoc Neurosci 74:1.26.1-27
Mundell, Nathan A; Beier, Kevin T; Pan, Y Albert et al. (2015) Vesicular stomatitis virus enables gene transfer and transsynaptic tracing in a wide range of organisms. J Comp Neurol 523:1639-63