We have identified three genes which, when mutated, can cause developmental malformations of the eye. These cause absence of the iris (or aniridia), and no eyes or small eyes. All three genes produce DNA-binding proteins which regulate the expression of other genes during development. We are exploring the complex regulation of these genes in cultured cells and in mouse and zebrafish models. Using existing information on what DNA sequences bind the aniridia gene PAX6, we can predict other targets for this gene and check their validity in the fish model. These targets are almost certainly conserved in mammals as well. Genes identified in this way are part of an interacting network that may include new genes causing other eye diseases. We are also exploring why no eyes and small eyes may not always manifest, even when the causative mutations are there. One protein that we have shown to play a role in this variability is called a chaperone because it helps newly formed and accidentally unfolded proteins to fold properly. The chaperone protein has a network of helpers that tells us how environmental factors influence gene function.