Developmental control of retinal growth; regulation of epithelial cell proliferation and cell size; cell biology of retinal adhesion.
Our research is focused on the retinal pigment epithelium (RPE), a tissue layer that is essential for coordinated maturation of neurons and glial cells in developing retinas, as well as for metabolic support of photoreceptor cells, the rods and cones, in mature retinas. Unlike most mammalian tissues, the RPE achieves its adult proportions through an increase in both cell number and cell size. Overall growth occurs in two partially overlapping phases, with cell division occurring primarily during the embryonic period and cell enlargement during postnatal development. We are specifically interested in genes that regulate the balance between cell proliferation and cell mass, and how these interact with the cell differentiation program. To examine these questions we are using a variety of approaches to study mice that have been genetically engineered to contain mutations in specific genes that control the cell division cycle. Our results have shown that in animals lacking the p27(Kip1) gene, an important cell cycle inhibitory protein, the RPE undergoes additional nuclear and cellular divisions. However, while the mutant epithelium contains approximately twice as many cells as wild-type controls, each cell in the monolayer is, on average, one-half normal size. This results in a tissue that displays few changes in its overall structure. On the other hand, retinas from these same p27(Kip1) “knock-out” animals exhibit large areas of detachment in which the physical interaction of the RPE with photoreceptor cells is severely disrupted. These studies have potential relevance for human diseases such as proliferative retinopathy and macular degeneration, in which there is an abnormal increase or decrease, respectively, in the number of RPE cells.