Body axis formation and organ morphogenesis depend critically on the ability of cells to migrate collectively to specific locations in the embro. While a number of different molecular pathways, such as Nodal, BMP, and Wnt, are known to govern embryonic development by controlling fate determination and gene expression, a different class of signals, including Wnt/PCP and Toddler, has been recently shown to play a crucial role during morphogenesis by regulating cellular movements. From a biophysics perspective, cellular movements, and changes of thereof, are caused by differential cellular forces, which are largely controlled at the molecular level by acto-myosin activity and cell-cell adhesion. However, the mechanisms by which signaling events control the endogenous distribution of cellular forces underlying cellular movements are unknown, mainly because of a lack of technologies allowing the measurement of cellular forces in vivo. The PI has recently developed novel force transducers (biocompatible oil microdroplets) that allow direct measurements of cell-generated mechanical forces within living embryonic tissues. This unique technology will be used in this project to study the biomechanics of zebrafish gastrulation in collaboration with Dr. Alexander Schier, whose lab recently discovered Toddler, a secreted peptide that signals through APJ/Apelin receptors and promotes mesendodermal cell movements during zebrafish gastrulation. Importantly, signaling through APJ/Apelin receptors has previously been shown to affect cell migration and biomechanics in different tissues. Given these findings, we hypothesize that Toddler signaling via Apelin/APJ receptors regulates the forces between mesendodermal cells, thereby affecting their migration. In order to test this hypothesis, we plan to (1) measure the cell- generated mechanical forces during ventral and dorsal mesendodermal ingression and migration, in wild type as well as in embryos with impaired Toddler signaling, and (2) establish how these forces are modulated in vivo via changes in acto-myosin contractility and cell adhesion levels, as well as characterize how Toddler signaling regulates these molecular processes to affect intercellular forces. This exploratory research promises to reveal how Toddler signaling affects the differential forces generated by mesendodermal cells during ingression and migration, linking for the first time a molecular pathway controlling morphogenetic movements to the biomechanical properties that ultimately drive cell migration. We believe this study will provide a framework to understand how signaling events guide cell migrations via the spatiotemporal control of tissue and cell biomechanics.
Some pre-natal malformations and the progression of several diseases in adults, including cancer, are caused by an imbalance in tissue biomechanics. This exploratory study is a first-of-its-kind and promises to shed light on the mechanical forces that sculpt the basic structure of the early embryo, and reveal how key signaling molecules control such forces. These results would transform our understanding of developmental processes and pave the way for the development of new tools to diagnose the wide range of diseases that alter tissue biomechanics, including cancer.
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