Vax genes and Wnt signaling

Our lab has a longstanding interest in how gradients of Eph RTKs function9-11, and are formed in the developing forebrain and eye12-14. We are focusing our current efforts on an analysis of the mechanism by which the Ventral Anterior Homeobox (Vax) transcription factors 1 and 212-14, which were cloned in our lab, establish dorsal-ventral (DV) polarity in the forebrain, including the DV gradients of EphB receptors in the eye. We have found that the Vax1 and 2 proteins, which are induced by the ventralizing morphogen Sonic hedgehog, ventralize the eye and forebrain by antagonizing dorsal differentiation. They achieve this by activating an internal promoter within the gene encoding Tcf7l2, a key effector transcription factor of the Wnt family of dorsalizing morphogens. This internal promoter drives expression of a truncated Tcf7l2 protein, which acts as a dominant-negative Wnt antagonist15. We are now using molecular genetics, cell biology, and high throughput screening to investigate this remarkable new regulatory mechanism16.

9. Brown, A., Yates, P.A., Burrola, P., Ortuño, D., Vaidya, A., Jessell, T.M., Pfaff, S.L., O’Leary, D.D.M., and Lemke, G. (2000) Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling. Cell 102: 77-88.
10. Reber, M., Burrola, P. and Lemke, G. (2004) A relative signaling model for the formation of a topographic neural map. Nature 431: 847-853.
11. Bevins, N., Lemke, G., and Reber, R. (2011) Genetic dissection of EphA receptor signaling dynamics during retinotopic mapping. J. Neurosci. 31: 10302-10310.
12. Bertuzzi, S., Hindges, R., Mui, S.H., O'Leary, D.D.M., and Lemke, G. (1999) The homeodomain protein Vax1 is required for axon guidance and major tract formation in the developing forebrain. Genes and Development 13: 3092-3105.
13. Mui, S., Kim, J. W., Lemke, G., and Bertuzzi, S. (2005) Vax genes ventralize the embryonic eye. Genes and Development: 19: 1249-1259.
14. Kim, J. W. and Lemke, G. (2006) Hedgehog-regulated localization of Vax2 control eye development. Genes and Development 20: 2833-2847.
15. Vacik, T., Stubbs, J. L., and Lemke, G. (2011) A novel mechanism for the transcriptional regulation of Wnt signaling in development. Genes and Development 25:1783-1795.
16. Vacik, T. and Lemke, G. (2011) Dominant-negative isoforms of Tcf/Lef proteins in development and disease. Cell Cycle 10(24): 419-200.