Relevance of proto-oncogenes as growth modulators in organogenesis of the mammalian embryonic kidney

Mammalian organogenesis constitutes a series of complex developmental processes which involve differentiation and rapid proliferation of pluripotent cells leading to the formation of a defined sculpted tissue mass, followed by a continuum of cell replication and terminal differentiation. These processes are modulated by various extracellular matrix (ECM) glycoproteins, ECM receptors, i.e., integrins, ECM degrading enzymes and their inhibitors, cell adhesion molecules (CAMs), intracellular cytoskeletal proteins, growth factors or hormones and their receptors, DNA-binding proteins/transcription factors and certain proto-oncogenes. The proto-oncogenes are growth regulatory genes normally expressed in mammalian cells, that with point mutations, amplification, chromosomal translocations, or DNA rearrangements acquire tumorigenic potential. They also encode for transmembrane receptor proteins of certain growth factors. These receptor proteins may either contain tyrosine or serine/threonine kinase intracellular catalytic domains, which conceivably endow proto-oncogenes with unique properties to regulate normal cell growth and proliferation subsequent to the binding of the putative ligand and phosphorylation of the receptor. The activities of the above described diverse group of macromolecules in embryonic development are intricately linked, and there is considerable variability in the cellular events and in the expression of various macromolecules, which are required predeterminants for the formation of individual organ systems. In other words, macromolecules with restricted genotypic or phenotypic expressions are relevant only to the morphogenesis of a particular organ system. Thus, "a morphogen is defined as a molecule that expresses its concentration gradient in a given tissue and alters the fate of target cells in a dose-dependent manner". This definition of a morphogen is applicable not only to proto-oncogenes, acting as receptors of certain ligands, but also to ECM macromolecules and their respective receptors, i.e., integrins, cell adhesion molecules and growth factors and their receptors. In the same vein, differential concentration gradients of these macromolecules in various regions of the same developing tissue would induce different specific cellular events, thus adding complexity to the differentiation processes that ultimately leads to regional specialization within a given organ system. Finally, the magnitude of expression of various morphogenetic