Grant: Discovery Grants Program - Individual

Determining the intricacies of the numerous signal transduction events that go on within and between cells is one of the most actively investigated areas in the field of cellular and molecular biology. Basic biological research has led to important breakthroughs, which have been capitalized on by the pharmaceutical industry. Although that industry is focused on human health and disease and driven by profit, the overall importance of these signaling events must be underpinned by the fact that they are responsible for initiating, shaping and maintaining the life of every living organism, regardless of whether or not it has a backbone. Historically, these pathways were once naively thought to unfold in a linear fashion, but as more pathways and their protein participants were discovered it was realized that a significant amount of communication exists between them. This crosstalk at nodes where the pathways intersect has made the study of any one pathway in isolation obsolete, and thus their identification has garnered significant attention especially in the signal transduction field of developmental cell biology. My interests and that of many other labs in Canada and abroad lie with a group of 19 Wnt proteins and a much smaller, but just as influential group of three Hedgehog proteins, which drive several signaling pathways that contribute to the embryonic development of almost every animal on Earth. Fertilized eggs divide repeatedly to produce a pool of cells, which differentiate along specific paths if and only if they can correctly interpret the combination and levels of the Wnt and Hedgehog ligands presented to them. In some instances this interpretation leads to the transition of one cell type that had been firmly attached to a membrane and its neighbors, into another that is highly migratory and aggressive in its ability to colonize other regions of the embryo or body in the case of the adult. These transitions occur several times during embryogenesis, but most people are probably more familiar with those associated with metastatic cancer, where in many instances fully differentiated cells later in life are reprogrammed mistakably due to having again received the same Hedgehog or Wnt ligands. To further complicate our understanding of the signal transduction events that go on within and between embryonic cells, we and others have recently found that in the absence of a Wnt protein, highly reactive oxygen species naturally generated by living cells and at levels that are not dangerous to them, can prime the Wnt signaling pathway in preparation for its full activation by the ligand. In the example of the differentiated cells this ability to prime a signaling pathway could have dire consequences especially to those cells that have inadvertently retrieved a Wnt ligand. My objectives are to first determine how the Wnt and Hedgehog pathways are activated during mouse and zebrafish embryonic development and then uncover the extent of the signaling crosstalk between the pathways at specific times, and finally to identify how the node(s) or other proteins in the pathways are affected by reactive oxygen species. I am confident that attaining these goals will lead to a better understanding of the communication crosstalk that ensures the correct flow of molecular information is made available to instruct one cell type to adopt a new fate. Towards that end, I expect that the publications and presentations of this basic biological research will be of significant interest and applicable to many areas of what worldwide is presently and will continue to be, a high profile and highly competitive field of developmental, cell, molecular and chemical biology.