Investigating the molecular basis of basement membrane specialisation and basal surface organisation during epithelial tissue development

Cells are the building blocks that make up our organs. Our goal is to understand how during development, epithelial cells, which are found in most of our organs, coordinate changes in their shape to generate complex three dimensional structures, including tubes, folds and cavities, vital for organ function. One of the reasons we are interested in epithelial cell and tissue shape control is because abnormal epithelial tissue organisation has been implicated in many diseases, including in colon, stomach, breast, and lung cancer, for example. To uncover how changes in cell shape can be coordinated across a tissue to generate a healthy, functioning epithelial structure, we will use the Drosophila (fruit fly) retina, where we can use a broad range of genetic tools to manipulate the function of candidate molecular machinery involved in cell shape control, while studying the effect these manipulations have on cells and tissue shape in a living animal, as the organ develops. With this powerful approach, we have recently discovered that cells can communicate with each other to coordinate changes in their shape through a molecule called Laminin, a gel-like substance that lines the bottom surface of cells in flies and human alike. Our objective is to further investigate this communication process in a simple animal system and understand how it helps coordinate the changes in cells that shape the tissues in our organs. This knowledge will help us comprehend how epithelial tissues develop in general and we hope, will contribute to better understanding the causes of diseases linked to abnormal epithelial tissue organisation and mutation in Laminins, which have been implicated in a range of pathologies in humans.

Our objective is to understand how epithelial cells coordinate the remodelling of their shape to generate a physiological structure in organogenesis. This is important because many diseases stem from epithelia, and abnormal epithelial tissue organisation is a hallmark of cancer. In healthy tissues, cells coordinate their polarity to generate a distinct apical and basal surface. To understand how epithelial structures arise in development, we need to establish the pathways that coordinate cells shape remodelling across both these tissue surfaces. While progress continues to be made in understanding how cells remodel their apical geometry to shape tissues, there is a significant knowledge gap regarding the mechanisms that promote cell basal geometry remodelling. In addressing this question, using the Drosophila retina as a tractable model system to study epithelial development, we have recently discovered a novel pathway in epithelial morphogenesis. In this pathway cells communicate through Laminin, a basement membrane factor, to coordinate remodelling of their basal geometry. Our aim is to characterise this novel morphogenetic pathway by establishing i) how cells interact to generate a pattern of Laminin-rich sites in their basement membrane, ii) how these sites recruit Integrin receptors to coordinate basal geometry remodelling across cells, and iii) how apical and basal geometry remodelling are coordinated to shape cells in three dimensions. The principles we uncover will be of general significance since cell shape remodelling drives morphogenesis across epithelial tissues and species.