Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling

Seven major cell–cell signaling pathways—Wnt, TGF-β, Hedgehog (Hh), receptor tyrosine kinase (RTK), nuclear receptor, Jak/STAT, and Notch—control the vast majority of cell fate decisions during the development of bilaterian animals (Gerhart 1999). Each pathway is used repeatedly during the development of a given organism, activating different subsets of target genes in different developmental contexts. These seven pathways are strikingly diverse in both their complexity and the biochemical mechanism of signal transduction, ranging from direct transcriptional regulation by the nuclear receptor proteins to the extended protein phosphorylation cascades characteristic of RTK pathways. Nevertheless, the primary consequence of signaling is the same: activation of specific target genes by signal-regulated transcription factors.

Recent work has revealed several surprising and fundamental commonalities in the transcriptional mechanisms by which these pathways control the expression of their target genes. In this review, we discuss transcriptional regulation by developmental cell signaling pathways, and suggest that three functional properties—activator insufficiency, cooperative activation, and default repression—are shared among the major pathways. Together, these three “habits” allow signaling pathways to strongly activate target genes in their proper context, while preventing their expression in all other cells. Such strict control over target gene expression explains an extraordinary feature of developmental cell signaling: the capacity of a single pathway to elicit a large variety of gene expression patterns, and hence to control the specification of a large variety of cell fates.