Dissecting a role for ZAK-beta in skeletal muscle development using genetics and embryology in zebrafish and Xenopus

During skeletal muscle development and repair, myogenic stem cells proliferate and, when triggered to do so, exit the cell cycle and fuse to form multinucleated myofibres. This process occurs both during embryonic development and during regenerative processes that happen when muscle is injured or in a disease-state, as occurs in muscular dystrophy. Cell signalling is an important trigger that regulates a myogenic cell’s switch from proliferation to differentiation. This project will investigate the role of a protein that is part of the MAPK signalling pathway, called ZAK-beta. The gene coding for this protein has recently been implicated in an inherited myopathy in humans and this project will use genetics and molecular embryology to determine any role for ZAK-beta in skeletal muscle development and repair.

The analyses in this project will be done in vivo using non-mammalian vertebrate animal models (Xenopus and zebrafish). Gene editing using CRISPR/Cas9 is very effective in frogs and fish and this gene targeting approach will be used to disrupt ZAK-beta in frogs and fish. Manipulating the FGF signalling with dominant negative and inducible FGF receptors to inhibit and overstimulate the MAPK pathway will be one approach to dissect the pathways that require ZAK-beta activity. IGF and EGF signalling will also be investigated in the context of ZAK regulation of myogenic development , growth and repair. The student will also gain experience using embryological manipulations of frogs embryos and generating genetic lines in zebrafish, as well as using cell and molecular assays to analyse signal transduction and gene expression.

We strongly encourage you to email the project supervisor prior to submitting an application to discuss your suitability for this project. Please email: [Email Address Removed]