Cdc42 and Rac1 in Pancreatic Tubulogenesis and Islet Formation

Abstract: Tubes form the basic structure of several organs like lungs, kidneys, glandular organs like the pancreas, mammary and salivary glands. Tube formation involves a series of dynamic and interdependent cellular processes, including cytoskeletal reorganization, assembly of intercellular junctional complexes, and cell polarization. Understanding how cells polarize and coordinate tubulogenesis during organ formation is a central question in biology. Tubulogenesis often coincides with cell lineage specification during organ development. Hence, an elementary question is whether these two processes are independently controlled, or whether proper cell specification depends on formation of tubes. To address these fundamental questions, we have studied the functional role of Cdc42 in pancreatic tubulogenesis. We present evidence that Cdc42 is essential for tube formation, specifically for initiating microlumen formation and later for maintaining apical cell polarity. Finally, we show that Cdc42 controls cell specification non-cell-autonomously by providing the correct microenvironment for proper control of cell fate choices of multipotent progenitors. To understand the process and importance of endocrine cell delamination and migration from the ductal epithelium, we used transgenic mouse models expressing the dominant active Cdc42 (Cdc42 DA) or the dominant negative Rac1 (Rac1 DN) in the insulin cells. Active Cdc42 enhanced E-cadherin and F-actin at the cell-cell contacts and blocked the delamination of newly formed insulin cells. The beta cell numbers were severely reduced and resulted in hyperglycemia. Expression of dominant negative Rac1 did not affect the delamination but impaired the subsequent migration and organization of islet cells. E-cadherin was enhanced in the cell-cell contacts of the transgenic islet cells expressing Rac1 DN. Our results describe the process of tube formation in glandular organs like pancreas and identified key regulators in the process. In addition, we show tube formation plays a crucial role in establishing correct microenvironment for proper cell fate specification. Bo