Biochemical principles of SMAD signaling across the animal kingdom

The bone-morphogenetic protein (BMP)-SMAD signal transduction pathway regulates fundamental cellular processes such as fate specification, tissue patterning, and stem cell homeostasis across metazoans and has a conserved signaling architecture. However, the quantitative dynamics of SMAD signaling and regulatory strategies governing pathway activity show a wide range of variation across developmental and stem-cell systems. In the present review, we summarize insights from six major biological contexts-Drosophila embryo, germline stem cells, and the larval and pupal wing discs; the Danio rerio (zebrafish) embryo; and human pluripotent stem cells-to compare how BMP signals are measured, manipulated, modeled, and integrated. We begin by outlining the canonical BMP signaling pathway and the mechanisms of BMP gradient formation across developmental systems, highlighting how conserved pathway components contribute to the formation of system-specific spatial profiles. We then summarize intracellular Smad dynamics and how endogenous pathway dynamics are measured through quantitative imaging of the phosphorylated Smad. Next, we examine how BMP signaling is interpreted through tiered transcriptional responses of downstream target genes. Next, we summarize the mechanistic and computational models of integrated gradient formation, signal transduction, and gene regulation across the presented systems. These insights reveal unifying design principles and performance objectives that govern BMP-SMAD signaling across species and cell types and frame open questions for future cross-species and translational studies.