Organization and function of the interface between cadherin and the cytoskeleton

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Cadherins are multifunctional adhesion receptors involved in animal development and tissue homeostasis. We are particularly interested in the role cadherins play in epithelia, the major tissue type found in animals. Cadherins link cells together at prominent contact points called adherens junctions. When cadherins do not function normally, epithelia collapse or develop abnormal shapes, which is often lethal to the animal. Cadherins can only function when they are linked to the cytoskeleton of a cell. This linkage is crucial to form and maintain adherens junctions. Moreover, adherens junctions and the cytoskeleton have to cooperate to shape and maintain tissues. Cadherins bind to several cytoplasmic factors including a-Catenin, a protein that we have studied in recent years, and that is the major linker between cadherin and the cytoskeleton. The importance of the linkage between cadherin and the cytoskelton is highlighted by the fact that loss of a-Catenin causes the same defects as loss of cadherin. However, the interface between cadherin/a-Catenin and actin is very complex as not only a-Catenin can bind to the actin filaments of the cytoskeleton, but has also several binding partners that can bind to actin. Much remains to be learned about how this interface operates to regulate epithelial development and stability. We have recently identified a new a-Catenin binding partner called Girdin that localizes to adherens junctions in the fruit fly Drosophila, the experimental model that we study, and in mammalian cells as was shown by a collaborator. Girdin can directly bind to actin. When Girdin is lost, actin organization is disrupted at adherens junctions and epithelia adopt abnormal shapes. The first aim of our proposed work is to develop a detailed understanding of how Girdin interacts with a-Catenin and what specific contributions Girdin makes to the function of adherens junctions and the organization of the actin cytoskeleton in epithelial cells. In a second aim we will explore the interactions between adherens junctions and the second major component of the cytoskeleton, microtubules. The ends of microtubules are linked to adherens junctions, an association presumed to be important for adherens junction formation and stability, but a detailed understanding of exactly how microtubules interact with adherens junctions and why this is important for normal epithelial development is outstanding. In order to gain an entry point and develop tools to study this association we will explore the function of a factor called PLEKHA7 in mammals and CG34383 in Drosophila. Work in mammalian cell culture suggests that PLEKHA7 links the ends of microtubules to cadherin and that compromising this link disrupts adherens junctions. An analysis of CG34383 in Drosophila will give us the unprecedented opportunity to investigate how this protein contributes to epithelial development in the context of a whole animal.