Cell-cell and cell-substrate adhesion molecules play a crucial role in guiding cells and axons along their paths during tissue and organ formation and the formation of the intricate patterns of nerve connections. Our interest is focused on adhesion molecules in each of the three major families: the integrin family of cell-substrate adhesion molecules, the cadherin family of cell-cell adhesion molecules, and members of the immunoglobulin superfamily (IgSF) of cell-cell adhesion molecules. The cytoplasmic domains of these adhesion receptors interact with signaling molecules and adaptor molecules that propagate signals initiated by adhesive interactions, in some cases directly altering the function of the adhesion molecule and in other cases initiating signal cascades that alter cell function in many different ways.

Our goal is to understand the molecular mechanisms through which rapid changes in the function of adhesion molecules occur. One aspect of this overall goal is to determine how adhesion molecules in the cadherin and integrin families are regulated by extracellular signals, giving rise to changes in cell motility and axon guidance. This latter set of goals focuses on secreted guidance cues in the nervous system such as chrondoitin sulfate proteoglycan Neurocan and the glycoprotein Slit. Another goal is to understand the role of the adhesion molecule P0, the smallest member of the immunoglobulin superfamily, in myelination of the peripheral nervous system. P0 is expressed by Schwann cells and is believed to mediate adhesion between successive membrane layers of the myelin scheath. Mutations in P0 give rise to Charcot Marie Tooth disease, a neurodegenerative disease of the peripheral nervous system.

The integrating theme of all our work is that extracellular ligands, such as axon guidance molecules, or intracellular effectors, such as kinases and phosphatases, give rise to changes in adhesion molecular function, regulating tissue rearrangements and axon targeting and outgrowth, and that mutations in adhesion receptors may alter function inappropriately, giving rise to disease. We are using in vitro cell culture models and ex vivo models, such as culture of intact neural retina, to investigate these problems. In these models, we use strategies that perturb specific protein-protein interactions among the signaling molecules associated with the cytoplasmic domain of adhesion receptors and the introduction of mutant forms of molecules thought to regulate adhesion molecules. This is followed by quantitative analysis of cell behavior and/or changes in cellular and tissue architecture.