Stages of Kidney Organogenesis

temporal coordination of numerous biomolecular interactions. Approaches geared toward elucidating the molecular and cellular basis of kidney development and branching morphogenesis have focused on the study of discrete molecules and signaling pathways by using genetic and in vitro approaches (reviewed in Refs. 11 and 71), more recently combined with microarray studies (66, 74, 75). To date, integration of this body of data at the protein, genetic, and cellular levels has proven difficult, and precise causal relationships mapped within a more general framework remain elusive. Moreover, apparent contradictions between in vitro and genetic experiments have so far limited our ability to assemble a complete mechanistic model. A seemingly opposite yet broader tactic that is emerging in the postgenomic field is to use a system-level approach. Genome-scale protein-interaction maps have been constructed in numerous organisms. Indeed, high-throughput data collection techniques are being applied with increased frequency across many systems, including the kidney. This organization of data into a graphical arrangement of nodes and links, where nodes depict molecules (proteins, nucleic acids, proteoglycans, etc.) and links delineate the interactions between them, encompasses a network. Many classes of networks exist within a cell or an organism; these may include gene expression, proteinprotein, metabolic, and signaling networks. It has been found that architectural features common to complex systems (which range from the Internet to societies to cells) result in a robust, relatively errortolerant network (2, 4). Obviously, construction of a topological and dynamic network of branching morphogenesis would require knowledge of all molecules involved in kidney development and an understanding of their intricate interactions. Although the kidney database of genes and proteins is far from complete, current in vitro and mutation data, albeit limited, support the presence of a network architecture that underlies the branching program (49). As our understanding of gene expression, protein-protein, and signaling pathways in branching morphogenesis progresses, organization of data into such a framework would enhance attempts to define, quantify, and model the structural and dynamic parameters that underlie branching morphogenesis. Combined with studies that aim to delineate the detailed roles played by specific molecules (Table 1), these two approaches may be able to provide complementary and converging viewpoints that would enable integration and a deeper understanding into the factors that control kidney development. Although branching during kidney development is the focus in this review, many of the issues are applicable to organogenesis in general.