The vertebrate eye is among the most exquisitely polarized of sensory tissues, and its axial patterning during development is essential to both its orderly connection to the brain and its mature function. Although the retina appears superficially uniform and featureless, it is in fact a highly ordered epithelium that displays gradients of signaling proteins and their receptors, enzymatic activities, and transcription factors. We wish to understand how these gradients are established during eye development. Our goal in this project is the functional analysis of genes that control axial patterning. The experiments of the proposal focus on Vax1 and Vax2, which encode two closely-related transcription factors that play key roles in the specification of the eye's dorsal-ventral axis. We will exploit a set of existing mouse mutants, and will also generate new mutants, in which the structure, expression, and activity of the Vax genes is systematically altered. We will use these genetic reagents, together with biochemical and cell biological assays, to perform a detailed dissection of Vax function during two distinct phases of eye development. We will identify and analyze the target genes whose expression is regulated by Vax 1 and Vax2 during both of these phases. We will study the mechanisms by which Vax2 activity within cells is regulated by the subcellular trafficking and localization of the protein. And we will identify the'protein partners that interact with, and modulate the activity of, Vax1 and Vax2. Together, these experiments will reveal the molecular mechanisms through which transcription factor gradients specify the Cartesian coordinates of the eye. Relevance: Our ability to interpret the light that falls onto the surface of the retina - to see the world around us - requires an ordered set of connections between the eye and the brain. Order within these connections is first established by the coordinate axes of the eye. The experiments of this proposal are designed to provide fundamental insights into the genetic and biochemical mechanisms through which these axes are organized - from top to bottom and from side to side - during development.
| Slavotinek, Anne M; Chao, Ryan; Vacik, Tomas et al. (2012) VAX1 mutation associated with microphthalmia, corpus callosum agenesis, and orofacial clefting: the first description of a VAX1 phenotype in humans. Hum Mutat 33:364-8 |
| Vacik, Tomas; Stubbs, Jennifer L; Lemke, Greg (2011) A novel mechanism for the transcriptional regulation of Wnt signaling in development. Genes Dev 25:1783-95 |
| Kang, Kyung Hwa; Lemke, Greg; Kim, Jin Woo (2009) The PI3K-PTEN tug-of-war, oxidative stress and retinal degeneration. Trends Mol Med 15:191-8 |
