A fundamental question facing developmental biologists and tissue engineers is: How do epithelial cells form the uniquely shaped structures (e.g. flat sheets, spherical cysts, elongated tubes) that are critical for tissue function? It is known that the architecture of virtually all epithelia is dependent upon coordinated adhesive interactions between individual cells and extracellular substrates. These interactions are mediated by transmembrane receptors that are linked to the cytoskeleton by cytoplasmic adapter proteins. Defective interactions between epithelial cells and their extracellular substrates are implicated in a wide variety of pathological conditions that include tissue fragility diseases and increased tumor invasiveness.

My laboratory is interested in the regulation of epithelial morphogenesis during development, with a specific interest in how extracellular matrix proteins, transmembrane receptors, and cytoskeletal adapters work together to specify tissue architecture. Although little is known about specific mechanisms that regulate epithelial cell morphology, these mechanisms are conserved between species and involve the localized deposition of molecules that contain adhesive and/or positional information. We have chosen a genetic approach, using screens to identify C. elegans mutants with defects in genes controlling epithelial differentiation. To date, we have identified and characterized hemicentin, an extracellular matrix protein with a modular structure (figure 1) that is involved in the differentiation of specialized epithelial cells in C. elegans and has 2 highly conserved orthologs in the human genome.

Where is hemicentin expressed?
We have constructed a functional fusion between hemicentin and green fluorescent protein (GFP), enabling us to monitor hemicentin-GFP localization in live animals during development. Hemicentin accumulates at sites where epithelial cells make long, line-shaped attachments to a number of tissues including specific uterine cells and subsets of neurons, including those involved in mechanosensation (figure 2).

Our current focus is on using molecular, genetic and biochemical techniques to identify the functional significance of hemicentin structural domains and on identifying cell surface receptors and other extracellular proteins that functionally interact with hemicentin.

The long-term goal is to understand the function of extracellular matrix proteins in the modification of epithelial cell architecture. Specific questions that we plan to address include: What are the roles of vertebrate hemicentins? How can hemicentin be used in the design of bioactive synthetic matrices to regulate the morphogenesis of engineered tissues?