Research in the Marciano laboratory is focused on understanding the cellular and molecular mechanisms of tubular and glomerular formation in health and disease.
Cellular and molecular mechanisms of tubulogenesis
One of the fundamental questions of developmental biology is: how do a group of cells orchestrate the complex changes, including proliferation, migration, sorting, and differentiation to form a polarized tubule? This is especially important in human biology as defects in these processes lead to diseases such as polycystic kidney disease. Currently our laboratory is studying the role of cell-cell adhesion molecules in tubulogenesis and kidney morphogenesis. We are using an in vitro 3-dimensional cell culture model and in vivo mouse genetics to study these processes in developing kidney tubules.
One family of cell-cell adhesion receptors, the cadherins, interacts via their extracellular domains to form adherens junctions between neighboring cells. Key regulators of cadherins are p120 catenin (p120ctn) and b-catenin, which bind to intracellular regions of cadherins and regulate cell-cell adhesion, signal transduction and gene transcription. We recently found that absence of the cadherin regulator p120 catenin (p120ctn) in mice leads to decreased cadherin levels with abnormal morphologies of early tubule structures (Marciano et al., 2011). Furthermore, p120ctn mutant mice develop cystic kidney disease, with markedly increased tubule diameter, cellular proliferation, and detached luminal cells. We are currently investigating the molecular mechanisms by which p120ctn and cadherin signaling control tubule formation and diameter.
Another focus of the laboratory is to identify how apical basal polarity and lumen formation is initiated in developing renal tubules. We have recently identified a mouse model in which these processes are disrupted (Yang et al., in press). Mice lacking Afadin, a nectin adaptor and Rap1 effector, have defects in establishing an apical surface and forming a continuous lumen. We are investigating the signaling pathways that mediate these defects and are identifying other essential pathways in initiation of tubulogenesis. We expect that these results will give insight into childhood developmental disorders such as congenital renal dysplasia. In addition, knowledge of these mechanisms may be important in acquired renal diseases of tubules.
Role of cell-cell adhesion in glomerular formation and function
Kidneys filter blood through highly specialized structures called glomeruli. The regulation of glomerular filtration is essential for life, and defects in this process cause glomerular disease and kidney failure. In recent studies we have found that mice lacking p120ctn in glomeruli develop focal segmental glomerulosclerosis, a common cause of renal failure in humans that is attributed to defects in the permeability barrier. We are currently examining the role of p120 catenin and other adhesion proteins for their role in the formation and maintenance of the filtration barrier using mouse genetics, cell culture, RNAi, and biochemistry. We expect that understanding these processes will give insight into normal glomerular development and the pathogenesis of various glomerular diseases.