The Role of Netrins and Their Receptors in Epithelial Mesenchymal Plasticity during Development

Transitions between mesenchymal and epithelial cells are underpinned by changes in motility, adhesion, and polarity. Netrins and their receptors can control each of these cellular properties, and are emerging as important regulators of epithelial mesenchymal plasticity (EMP). Netrins were first identified in the worm Caenorhabditis elegans as secreted chemoattractants/repellents that could guide migrating mesodermal cells and axonal growth cones. Orthologues were subsequently found to play conserved roles in vertebrates and in the vinegar fly Drosophila. In the years that have followed it has become clear that, in addition to chemotaxis, netrin pathways have a number of other biological roles, many of which are directly relevant to the processes of EMP. Netrins and their receptors regulate morphogenesis of epithelial branched structures in the lung, mammary gland, pancreas, and vasculature, and can also promote the loss of epithelial structure. More recently they have been shown to drive apicobasal cell polarization events in vertebrates, flies, and worms. Given these many and varied roles in regulating epithelial morphogenetic events, together with their well-established roles in cell motility, netrins are likely to remain an important future avenue for EMP research.