Gene regulatory networks and embryonic specification

Abstract

Eric Davidson embarked on the study of sea urchin development more than 40 years ago, with his initial efforts focused on studying the animal's nucleic acid properties through hybridization—studies that, amazingly enough, began to delineate the early logic of how to think about development (1). However, Davidson was always driven by biology: in his case, by a desire to understand the molecular basis of sea urchin development. In the intervening years, Davidson and his colleagues came to understand the biology of sea urchin development at a uniquely deep level, and this knowledge was the driver and integrator of subsequent developmental studies. Over the past 15 years or so, Davidson arrived at the realization that development was hardwired in the gene regulatory logic of the genome and that determination of this logic would require a systems approach (i.e., global analyses, rather than the study of one or a few genes or proteins at a time). He also came to understand that the systems approach to development required (i) determination of the complete sea urchin genome sequence, to compile a complete “parts list” of sea urchin genes, especially those encoding transcription factors; (ii) an understanding of the deep logic of how individual genes are regulated by transcription factors through their cis-regulatory elements; and (iii) a delineation of the dynamics of complete gene regulatory networks (GRNs) specifying the distinct stages of sea urchin development. Complete GRNs—the dynamic network relationships of all relevant transcription factors—are essential because the genomic regulatory logic is so complex that inferences from incomplete networks can be misleading or inadequate. For each of these challenges, Davidson and his colleagues carried out groundbreaking work. Davidson was almost single-handedly responsible for initiating the sea urchin genome project, and he certainly inspired what was perhaps the most thorough annotation of any genome at that time (2). His group specified, in detail, the cis regulation of the developmentally regulated endo-16 gene and demonstrated the fascinating logic and complexity of this regulatory circuit (3). Finally, Davidson and his associates pioneered the preliminary delineation of a variety of GRNs and their specification of sea urchin larval development (see ref. 4).