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BMP mophogens direct growth and fate As shown in classic fate-mapping studies, tissues and organs arise from specific regions of the embryo. Work over the past few decades has identified molecular players directing this choreographed development. Bone morphogenetic proteins (BMPs) and their antagonists establish domains in developing embryos. Bier and De Robertis review historical events for key discoveries in this area. They go on to lay out the current understanding of how diffusible morphogens form gradients to subdivide germ layers into distinct territories and organize body axes, regulate growth, and maintain stem cell niches. Science, this issue 10.1126/science.aaa5838 BACKGROUND Classic embryological studies showed that diffusible factors (morphogens) influence cell fate during dorsal-ventral (DV) axis patterning. Subsequently, mathematical analyses applied reaction-diffusion equations in a theoretical framework to model how stable gradients of morphogenetic factors might be created in developing cell fields, according to the laws of physical chemistry. This work suggested mechanisms by which such gradients form and are read in a threshold-dependent fashion to establish distinct cellular responses. As highlighted in this Review, these pioneering experimental and intellectual insights laid the groundwork for more recent studies that have elucidated the mechanisms by which morphogen gradients are generated and stabilized by molecular feedback circuits. ADVANCES The molecular players involved in early DV patterning uncovered over the past two decades constitute a highly conserved cohort of extracellular factors that regulate bone morphogenetic protein (BMP) signaling. A key insight was the identification of the homologous proteins Short gastrulation (Sog) and Chordin as BMP-binding proteins in Drosophila and Xenopus 20 years ago. Since then, analysis of this patterning system has led to dramatic advances in our understanding of the molecular mechanisms regulating early DV axis specification. Elements of this pathway include secreted BMP ligands and BMP antagonists, as well as extracellular metalloproteinases that cleave and inactivate BMP antagonists. Identification of these and other accessory proteins provided strong support for the proposal that an inversion of the DV axis had occurred between arthropods and vertebrates. Analysis of how these components are deployed in an array of species with divergent developmental strategies has deepened our understanding of this ancestral DV patterning biochemical pathway. These comparative studies have shed light on the broader question of a how a conserved core pathway can be modified during evolution to accommodate different forms of embryogenesis while maintaining common output effector functions. In addition, advances in computational analysis have provided the necessary tools to analyze BMP-mediated signaling in quantitative terms and have provided important insights into how this patterning process is integrated with cell proliferation and tissue growth. One such insight is the identification of expanders (such as Pentagone and Sizzled), which are secreted molecules typically produced at the low end of a gradient that stabilize the ligand, scaling the gradient to the growth of tissues. OUTLOOK An important unanswered question is how morphogen gradients form and function reliably in the face of intrinsic signal-degrading processes to achieve consistent developmental patterning and growth. One testable hypothesis, based on the “wisdom of crowds” concept, that may shed light on this challenging problem is that several independent features of morphogen gradients can be read in parallel by cells and can also serve as inputs to an array of feedback modules that integrate instantaneous levels of signaling, perform time averaging of signals, and act locally to coordinate signaling between neighboring cells. A consensus-based estimate of the relative position of a cell may be reached by deploying multiple parallel feedback modules. In addition, it will be important to determine the roles of mechanisms, such as free or facilitated diffusion in the extracellular space; exosomes; and cytonemes in morphogen gradient function. Understanding the mechanisms by which morphogen-mediated patterning systems evolve to maintain key elements of overall body design while allowing for a marked diversity in the spatial deployment of various subsets of signaling components is another compelling challenge. Such studies should better illuminate the precise nature of highly constrained developmental processes and delineate more fluid features of the networks that permit remodeling of core components to meet the specialized selective needs of particular organisms. These future studies should refine and strengthen one of the best paradigms for understanding development. Conserved BMP-mediated patterning of the DV axis. Gradients of proteins in vertebrates (left: blue Chordin stain) and invertebrates (left: red/yellow Sog stain) initiate patterning along the DV axis. These gradients are then read to establish distinct zones of gene expression within the central nervous system (right: dpp, yellow; msh, red; ind, green; vnd, blue). CREDITS: CHORDIN GRADIENT (LEFT) COLORED AND MODIFIED BY PHOTOSHOP FROM FIG. 3A OF J. L. PLOUHINEC ET AL., PROC. NATL. ACAD. SCI. U.S.A. 110, 20372–20379 (2013); SOG GRADIENT (RIGHT) MODIFIED BY PHOTOSHOP FROM FIG. 1B′′ OF S. SRINIVASAN ET AL., DEV. CELL 2, 91–101 (2002) Bone morphogenetic proteins (BMPs) act in dose-dependent fashion to regulate cell fate choices in a myriad of developmental contexts. In early vertebrate and invertebrate embryos, BMPs and their antagonists establish epidermal versus central nervous system domains. In this highly conserved system, BMP antagonists mediate the neural-inductive activities proposed by Hans Spemann and Hilde Mangold nearly a century ago. BMPs distributed in gradients subsequently function as morphogens to subdivide the three germ layers into distinct territories and act to organize body axes, regulate growth, maintain stem cell niches, or signal inductively across germ layers. In this Review, we summarize the variety of mechanisms that contribute to generating reliable developmental responses to BMP gradients and other morphogen systems.

BMP gradients: A paradigm for morphogen-mediated developmental patterning