![]() The distributions of the diffusing molecules are determined by the relative stoichiometry of diffusing particles and binding sites, by the affinity of the particles for the surface components and by surface non-uniformities. Surface diffusion is a process by which molecules move along surfaces by jumping between nearby low affinity binding sites. ![]() It is not apparent how unconstrained passive diffusion could generate extracellular gradients that precisely match the universe of spatial and temporal complexities that development creates.Īnother possibility is that constraints exist that can shape diffusion-generated distributions of extracellular morphogens. Although mathematical simulations have been developed that mirror morphogen distributions, they are in general formulated to mathematically flat surfaces, they do not contend with the complexities of changing topologies, and they depend on unsubstantiated parameters such as extracellular fluid volume, effects of interactions with extracellular components and boundaries, and rates of synthesis and degradation ( Lander, 2007). Concentration gradients of morphogens presumably must reflect these evolving conditions in real time. Tissues have complex shapes, and the relative sizes and spatial relationships between signaling centers and their fields of target cells change constantly during development. There are a number of reasons to have reservations about this mechanism. It has long been assumed that morphogens are released into extracellular fluid by producing cells, and that they move away by passive diffusion until they encounter receptors on receiving cells. We can also make the following assertion: that its economy and virtuosity can only be possible because of the precision with which it can be regulated in space and time. The general model here is that these morphogen signals constitute the vocabulary of a universal language of development, and we can marvel at the elegance of a system that produces such a vast array of different forms with so few components. Populated with multiple signaling centers that generate distinct spatial gradients, organ systems develop subject to the sum of the morphogen activities. Rather, they act locally, produced in every organ system by groups of cells (signaling centers / developmental organizers) that are designated to make a particular morphogen in an appropriate amount, place and time. Available evidence suggests that the Wnt, Hh, BMP, FGF, EGF and Notch/Delta signaling systems operate in most (or all) organ systems, but that they do not act systemically to script development and morphogenesis. They include the Wnt, Hedgehog (Hh), Bone morphogenic protein (BMP), Fibroblast growth factor (FGF), Epidermal growth factor (EGF), and Notch/Delta proteins whose structures and functions are conserved across the animal kingdom. ![]() They are each produced by discrete sets of cells, they disseminate across adjacent regions to form concentration gradients, and as graded positional cues, they elicit concentration-dependent responses in the cells that regulate growth and patterning. One of the great successes of developmental genetics has been the identification and characterization of morphogen proteins, molecules that transmit positional information in animal tissues. Instead I address the nature of position information and its distribution. The interpretation and execution of programmed responses are issues of signal transduction and cell biology that will not be considered here. Starting from the premise that some form of positional information directs the development of spatial patterns ( Wolpert, 2016, 1969), then we might describe our interest as seeking to understand the form in which positional information is encoded, how it distributes in space and time, and how it is interpreted. The conceit of the cell and developmental biologist is that these processes are knowable and can be defined in ways that match conditions and context to outcome. In contrast, the processes that generate shapes and patterns in biology control space and time with precision and reproducibility, despite the many uncontrollable variations in parameters that might influence them. We understand that the apparently infinite variety of snowflakes arises from unique combinations of atmospheric temperature and humidity and properties of initiating particles, and it is accepted that the number of these combinations is unknowable. Although the diversity of forms in the animal and plant kingdoms may not rival the number of shapes of snowflakes, it is nevertheless vast.
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