The extracellular matrix (ECM) is a key component of the cellular microenvironment and a driving force in development. Cells as diverse as neurons, stem cells, epithelia and glia, interact with the matrix resulting in localized activation of signaling pathways and cytoskeletal rearrangements. Depending on cell type and context, these interactions drive changes in cell fate, cell migration, and cellular architecture (such as polarization and process extension). Cell-matrix interaction also has a significant impact on the microenvironment itself, and is required for organization of the matrix into specialized basement membranes. Loss of this pivotal connection may represent a fundamental defect in the pathology of congenital muscular dystrophy (muscle, eye, brain disease) as well as other eye related defects.
Our current approach is to analyze the function of focal adhesion kinase (and close family member Pyk2) in conditional knockout mouse models as a starting point for understanding the intermediate signaling programs that unite the cell surface with the cytoskeleton. FAK in particular represents a signaling node, and analysis of its function and regulation may provide an important window into cellular function and pathology. We are also addressing other kinases that may regulate cytoskeletal attachment to points of adhesion such as integrin-linked kinase (ILK) and src family kinases (SFK).
Our recent model system of choice is the developing mammalian eye, given its wide array of cell types and the exquisite interplay of inductive events that drives eye morphogenesis. Furthermore, many of the major blinding disorders have no cure. Knowledge of how progenitor (and later born) cells respond to both adhesion and growth factor signals in the local environment may provide important biological insight into the pathology of these disorders.