Analysing the role of FGF signalling in pluripotency and skeletal muscle development.

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During development, totipotent stem cells give rise to a host ofspecialised, differentiated cell types. This process involves theprogressive restriction of developmental potential, and requires the highlycoordinated activation of sets of regulatory genes in specific groups ofcells in the developing embryo in response to cell signalling. Thefibroblast growth factor (FGF) signalling pathway is an importantregulator of gene expression during development. Our previous workindicates that FGF signalling activates and maintains the expression ofkey developmental regulators, such as the transcription factor MyoD; amyogenic regulatory factor that can orchestrate the process ofdifferentiation of skeletal muscle cells from stem cells. During vertebratedevelopment skeletal muscle cells arise from a pool of stem cells in theposterior of the developing embryo. Recent evidence indicates thatproperties of stem cells are regulated by a number of pluripotencyfactors, including Oct4, c-Myc, Lin28, and Nanog. This project willinvestigate the interplay of FGF signalling, MyoD and pluripotency factorsin muscle development in vivo using non-mammalian vertebrate animalmodels (Xenopus and zebrafish).This project will take make use of the advantages of frog and fishembryos for investigating cell lineage, cell signalling and gene expressionduring development. We will make use CRISPR/Cas9 mediated geneediting in frogs and fish to investigate the role of the FGF signalling andthe pluripotency factors c-Myc, Lin28, and Vent2 (nanog) in skeletalmuscle development. Manipulating the FGF signalling usingpharmacological inhibition to inactivate and inducible FGF receptors tooverstimulate the pathway will be the initial approach to uncovering theregulation of muscle determination, maintenance and differentiationduring development. The student will also undertake someembryological manipulations of frogs embryos to determine thepluripotent nature of the cells in the posterior mesoderm.