Grant: Operating Grant

The eyes form from extrusions of the brain. These complex tissues must subsequently fold and reorganize into a multilayered tissue that includes blood vessels. To do this, it forms a hole (fissure) located in the bottom-most retina at the 6 o'clock position. During embryo development, if the fissure fails to close, a portion of the lower retina dies, with such severe birth defects causing blindness. Collaborative research between Lehmann and Waskiewicz laboratories has identified evidence for a novel opening in the top-most region of the forming eye, which challenges the current model that the eye forms with a single fissure in the bottom of the retina. Patients with 'superior colobomata' display an opening in their upper retina and iris, with such defects leading to profound blindness. Using a vertebrate model organism, Zebrafish, we have identified a structure that forms in the top-most retina and has the properties of a temporary divider between cells. This research will investigate the function of this structure, first using microscopes and living zebrafish embryos to see if cells use this structure as a type of 'gatekeeper' to divide the forming eye into two equal halves (Aim 1). We will then investigate the genetic pathways that specify where this structure will form and when it will close (Aim 2). Finally, we will attempt to determine which mutations cause superior colobomata in humans. We have determined the DNA sequence of four patients with this disorder, thereby identifying candidate genes in causing superior colobomata. We will determine which mutations are likely to be disease-causing by creating animal models that lack the function of each of these mutated genes (Aim 3). These three aims will elucidate the genes that cause this newly discovered blinding disorder.