UC Davis

Sight relies on the integrity of the photoreceptor cells of the retina (rods and cones), and damage to these cells results in irreversible vision loss. Several degenerative diseases affect cones specifically, including age-related macular degeneration (AMD), one of the leading causes of blindness worldwide. A promising therapeutic strategy to restore vision in these patients is photoreceptor replacement, but our ability to produce cones in vitro is limited. Humans and other primates have a specialized region of the central retina called the fovea—the region affected by AMD—that contains the highest density of cones. This cone dominance is a sharp contrast to the majority of the retina, where rods outnumber cones 20:1. All the neurons of the retina (including rods and cones) are born from a single population of multipotent progenitors. However, the molecular mechanisms that dictate why the foveal progenitors differentiate into high yields of cones and not rods are unknown. A more complete understanding of these factors can be used to optimize existing stem cell protocols and increase cone production in vitro. In my collection of published work, I explored various molecular mechanisms that contribute to neural fate specification, including molecules of the retinoic acid pathway and microRNAs (miRNAs). My research focused primarily in the retina. I began by reviewing foveal development and curating the current knowledge of the steps towards its specification and maturation. The mechanisms driving foveal development are widely unknown, so I sought to study the fovea in the human and nonhuman primate. The La Torre lab is just three miles down the road from the California National Primate Research Center, priming us for access to nonhuman primate tissue across gestation. With these rhesus macaque tissues, I characterized retinal development and identified key stages of neurogenesis. I also showed that the expression patterns of molecules in and associated with the retinoic acid pathway, including CPY26A and FGF8, are not conserved between chicken and primate. Whereas in the chicken retina, these molecules contribute to the specification of the high acuity area, they are not fovea-specific in the primate retina. I continued to explore the role of miRNAs in fate specification through analyzing of the miRNA landscape across the developing nonhuman primate retina. I further validated those miRNAs found to be highly differentially expressed in the human retina. I reviewed oscillation patterns of miRNAs and the role in retinal development. Given that the cortex shares a similar developmental pattern with the retina, also having a progenitor population that all the neurons descend from in a stereotypic sequence, I explored how the Notch pathway and miRNAs influence fate specification in the mouse brain. Together, these studies identify a subset of the molecular mechanisms that drive neural differentiation and will inform future research on increasing the cone production in stem cell protocols with an ultimate goal of restoring vision in patients affected by optic neuropathies.