Gastrulation employs morphogenetic movements to organize the basic body plan of all metazoans. This proposal is for studies on one of those remarkable morphogenetic changes, an epithelial-mesenchymal transition (EMT), which occurs in all organisms that have mesoderm. The project will explore regulatory mechanisms that (1) trigger the EMT through a """"""""pre-EMT gene regulatory network"""""""" (pre-EMT CRN), (2) carry out the regulatory instructions of that GRN using endocytosis and exocytosis as important mechanisms in the transformation from the epithelial to a mesenchymal phenotype, and (3) assemble a new """"""""post-EMT gene regulatory network"""""""" (post-EMT-GRN) necessary for mesenchymal cells to execute their new functions. Because these mechanisms involve cell transitions, many disease states co-opt, at least partially, the pathways under scrutiny, making this investigation more broadly significant. The three Specific Aims are:
Specific Aim I : To discover how an EMT is regulated. Micromeres, the mesenchyme precursors in the sea urchin embryo, become specified under the control of the micromere gene regulatory network. That GRN changes to become the pre-EMT GRN just proximal to EMT and controls the morphogenetic change. Central to this Specific Aim is the observation that regulated expression of Snail and Twist not only control cadherin transcriptional downregulation, but also regulate endocytosis of the epithelial membrane, and simultaneously regulate exocytosis of the mesenchymal membrane components at EMT.
Specific Aim II : To discover how epithelial cells shift phenotypically to a mesenchyme cell. At EMT, the plasma membrane is completely remodeled by endocytosis-exocytosis.
This Aim will establish how endocytosis and exocytosis of the plasma membrane is regulated at EMT. Central to this Aim is the observation that at EMT bulk membrane replacement occurs by endocytosis of epithelial components while at the same time mesenchymal membrane components are inserted by regulated exocytosis.
Specific Aim III : To assemble the post-EMT gene regulatory network. Once the mesenchyme cell arrives in the blastocoel, it no longer uses the pre-EMT GRN.
This Aim i s to discover how that network undergoes change at EMT. Central to this Aim is the observation that new receptor tyrosine kinase (RTK) signal transduction mechanisms are inserted into the nascent mesenchyme cells. Our hypothesis is that this signal transduction event is essential for the switch from the pre-EMT GRN to the post-EMT GRN. The discoveries made in these three Specific Aims will advance our understanding of an epithelial- mesenchymal transition which is conserved throughout the animal kingdom, and is at least partially co-opted :or invasive activities of metastasizing tumors.
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