Development of the tubular nephron

Abstract

The renal tubule derives from two embryological structures: the metanephric mesenchyme and the ureteric bud. Tubulogenesis occurs in these two structures through somewhat different processes. The proximal through distal tubule of the nephron arises through compaction of previously unpolarized cells derived from the metanephric mesenchyme, whereas the collecting system arises through branching morphogenesis of an existing epithelial structure (the ureteric bud). Recent evidence from in vitro models using renal epithelial cells that undergo tubulogenesis and branching morphogenesis in three-dimensional collagen gels have shed light on the likely roles of growth factors, the extracellular matrix, and matrix-degrading proteinases in renal development. Differential effects of several growth factors (hepatocyte growth factor [HGF], transforming growth factor-alpha and -beta [TGF-alpha, TGF-beta], and epidermal growth factor [EGF]) suggest a mechanism for regulating the degree of tubule formation and branching events during collecting system development. Another model, the MDCK cell "calcium switch," is useful for studying the assembly of intercellular junctions and development of apical-basolateral polarity such as occurs during compaction of mesenchymally derived cells in developing renal tubules. Recent work with this model suggests that the assembly of intercellular junctions is regulated by classical signaling mechanisms including those involving intracellular calcium and calcium-dependent protein kinases. Together with organ culture studies of the embryonic kidney and analysis of genetically engineered mice, these models should allow dissection of specific molecular pathways in tubulogenesis.