Important biomedical applications, as well as advances in basic biology, require a detailed understanding of pattern formation in embryonic development. In contrast and complement to the current focus on biochemical control factors, our lab seeks to understand and learn to manipulate evolutionarily-conserved endogenous static membrane voltage gradients and ion fluxes which control cell fate and morphogenesis. During experiments on the role of K+ fluxes in embryonic development, we discovered that specific modulation of the activity of Katp channels (K+ channels with crucial roles in metabolism, diabetes, and cardioprotection) induces ectopic eye tissue in frog embryos. The phenotypes range from isolated retina tissue and lenses, to complete eyes formed in many ectopic locations (including on the gut and tail). This is a very exciting finding because it 1) identifies a novel patterning role for an ion channel of high biomedical relevance, 2) reveals a molecular entrypoint into a completely novel aspect of eye development that may cause revisions of current models of eye induction, and 3) provides a new way to control cell fate (via modulation of K+ flux) in somatic cells, which has applications in the production of eye tissue in therapeutic applications. We propose to make breakthroughs in this important and highly novel area through a unique convergence in our lab of molecular biology, biophysics, and functional physiology techniques in a number of tractable model systems such as Xenopus laevis. Through five aims that use established techniques and reagents to test molecular hypotheses about the mechanisms of ectopic eye induction, we will understand the interaction of this event with the endogenous eye-forming pathways, discover exactly when, where, and how the ectopic eyes are induced, determine whether the ectopic eyes are functional, and identify novel genes linking Katp activity to the eye gene cascade.This work has high relevance to the AED and the missions of the Eye and General Medical Sciences Institutes because we propose to utilize powerful techniques in a tractable model animal to produce wide-reaching and important biomedical advances in understanding, preventing, and repairing birth defects and degenerative diseases of the visual system. ? ? ?
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