Bridging Dynamic Signaling and Somite Morphogenesis

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DESCRIPTION (provided by applicant): Somitogenesis is a dynamic process that integrates global and local signaling with cell morphogenesis to produce an ordered array of metameric units, or somites, along the axis of vertebrate embryos. The goal of this project is to understanding how the read out of Notch, Fgf, Wnt and Retinoic acid pathways is combined to influence cell behavior mediated by protocadherins during somite boundary formation. A Xenopus explant system will be developed to visualize the behavior of cells within anterior or posterior somite compartments under normal and experimental conditions. The role of a novel protocadherin, paraxial protocadherin 2 (PAPC2), in establishing changes in cell-cell interactions at somite boundaries will be examined using this explant system. Finally, the enhancer regions controlling PAPC2 expression at forming somite boundaries will be isolated to further understand how input of signaling in the presomitic mesoderm positions expression of genes that act at boundary formation. Changes in protocadherin expression as well as misregulation of Wnt, Fgf, Notch, and Retinoic acid signaling pathways are seen during cancerous tumor growth and metastasis. Understanding the way these pathways are integrated during development to change cell behavior will provide strong experimental evidence for creating informed models that will help to elucidate the role of these signaling pathways in the progression of disease. Many ofthe genes that cause growth and establishment of tumors are also involved in the early development of embryos. Basic research into the ways cells use genes and the proteins they produce during development provides necessary tools for predicting how cancerous cells are using the same genes to establish tumors within specific tissues and to metastasize, releasing cells into the body that will invade new tissues. Ultimately, we hope to determine how genes are regulating cells' that are undergoing changes in adhesion during development and apply these findings to understanding the advanced stages of invasive forms of cancer. In solid tumors, certain proteins may cause cells to stick to one another, while in cases of metastasis, these same proteins may be lost from cells, allowing cells to migrate away from the site ofthe initial tumor. When cancerous cells invade new tissues, these adhesion proteins may be produced again and determine what type of tissues cancer cells can adhere to and form tumors in. By understanding how major gene pathways control adhesion in a developmental context, we will more fully understand how these genes control cell behavior during cancer establishment and progression.