HISTOGENESIS OF EPITHELIAL CELLS IN THE KIDNEY

Epithelia have similar structure and function in all organs where they are found, including respiratory, gastrointestinal and genitourinary tracts. A stereotyped architecture of tightly adherent communities of cells, with unique membrane and cytoplasmic domains distinguishes epithelia from all other fundamental tissue types. In addition to a singular generalized form, all epithelia contain a similar complement of proteins not found in other classes of cells. We propose that this common epithelial phenotype is directed by a few specific regulatory genes, perhaps even a single "master gene" in all epithelia regardless of lineage. In order to isolate a gene that regulates the epithelial phenotype, we are studying the genetic mechanisms of kidney epithelial histogenesis. Unlike most other epithelia which extend from preexisting epithelia, kidney cells are derived de novo from mesenchyme, a cell type entirely distinct in architecture and specific proteins. It is unlikely that each step in the conversion of mesenchyme to epithelia, requiring expression os hundreds of new proteins and suppression of others, is regulated independently; rather, a genetic switch must activate the epithelial program. Consequently, during genesis of kidney tubules genes controlling epithelial identity should be expressed in high concentration, allowing for their isolation. To identify epithelial master genes we will reproduce in vitro the conversion of mesenchyme to epithelium. DNA extracted from mesenchymal cells transitional to epithelia should contain activated regulatory genes. We will then introduce this DNA into naive mesenchymal cells and identify master genes by isolating single cells that change phenotype conversion from this cell. These studies will identify a gene that controls the epithelial phenotype. We will be most interested to examine expression of this gene in epithelia with abnormal development. For example, renal dysplasia and Wilms tumor are congenital abnormalities where pre-kidney mesenchyme fails to differentiate into epithelia and instead forms cartilage, bone and muscle. In both of these diseases it is possible that epithelial regulation is defective. More generally, isolation of an epithelial master gene will reveal a mechanism of organogenesis in derivatives of all three germ layers and in tissues as varied as the descendants of the neural crest.