1998 Warkany lecture: signaling pathways in development

Cell-cell signaling pervades all aspects of development, not just in vertebrates, but in all animals (metazoa). It is a typifying characteristic of the major multicellular life forms, animals, plants, and fungi, which diverged about 1.2 billion years ago from a common ancestor descended from a lineage of unicellular life forms. In metazoa, at least 17 kinds of signal transduction pathways operate, each distinguished by its transduction intermediates. Five kinds predominate in early embryonic development, namely, the Wnt, TGF-beta, Hedgehog, RTK, and Notch pathways. Five more are used in late development, and seven more in the functions of differentiated cells. The pathways must have evolved and become conserved in pre-Cambrian times before the divergence of basal members of most of the modern phyla. In metazoan development and physiology, the responses of cells to intercellular signals include cell proliferation, secretion, motility, and transcription. These responses tend to be conserved among metazoa and shared with unicellular eukaryotes and in some cases even with unicellular prokaryotes. Protein components of the responses date back 2 billion years to ancestral eukaryotes or 3 billion to ancestral prokaryotes. Each metazoan developmental process consists of a network of signals and responses, and many of these networks are conserved among metazoa, for example, by insects and mammals. The study of model organisms, even of nonvertebrate groups, is expected to continue to contribute greatly to the understanding of mammalian development and to offer opportunities to analyze the effects of toxicants on development, as well as opportunities to devise incisive assays for toxicants.