It is widely accepted that the growth and regeneration of tissues and organs is tightly controlled. Although experimental studies are beginning to reveal molecular mechanisms underlying such control, there is still very little known about the control strategies themselves. Here, we consider how secreted negative feedback factors (“chalones”) may be used to control the output of multistage cell lineages, as exemplified by the actions of GDF11 and activin in a self-renewing neural tissue, the mammalian olfactory epithelium (OE). We begin by specifying performance objectives—what, precisely, is being controlled, and to what degree—and go on to calculate how well different types of feedback configurations, feedback sensitivities, and tissue architectures achieve control. Ultimately, we show that many features of the OE—the number of feedback loops, the cellular processes targeted by feedback, even the location of progenitor cells within the tissue—fit with expectations for the best possible control. In so doing, we also show that certain distinctions that are commonly drawn among cells and molecules—such as whether a cell is a stem cell or transit-amplifying cell, or whether a molecule is a growth inhibitor or stimulator—may be the consequences of control, and not a reflection of intrinsic differences in cellular or molecular character.

Many patterns of cell and tissue organization are specified during development by gradients of morphogens, substances that assign different cell fates at different concentrations. Gradients form by morphogen transport from a localized site, but whether this occurs by simple diffusion or by more elaborate mechanisms is unclear. We attempt to resolve this controversy by analyzing recent data in ways that appropriately capture the complexity of systems in which transport, receptor interaction, endo- and exocytosis, and degradation occur together. We find that diffusive mechanisms of morphogen transport are much more plausible-and nondiffusive mechanisms much less plausible-than has generally been argued. Moreover, we show that a class of experiments, endocytic blockade, thought to effectively distinguish between diffusive and nondiffusive transport models actually fails to draw useful distinctions.

The dorsoventral axis of the Drosophila embryo is patterned by a gradient of bone morphogenetic protein (BMP) ligands. In a process requiring at least three additional extracellular proteins, a broad domain of weak signaling forms and then abruptly sharpens into a narrow dorsal midline peak. Using experimental and computational approaches, we investigate how the interactions of a multiprotein network create the unusual shape and dynamics of formation of this gradient. Starting from observations suggesting that receptor-mediated BMP degradation is an important driving force in gradient dynamics, we develop a general model that is capable of capturing both subtle aspects of gradient behavior and a level of robustness that agrees with in vivo results.

Partial diferential equations and auxiliary conditions governing the activities of the morphogen Dpp in Drosophila wing imaginal discs were formulated and analyzed as Systems B, R, and C in [7] [9] [10]. All had morphogens produced at the border of anterior and posterior chamber of the wing disc idealized as a point, line, or plane in a one-, two-, or three-dimensional model. In reality, morphogens are synthesized in a narrow region of finite width (possibly of only a few cells) between the two chambers in which diffusion and reversible binding with degradable receptors may also take place. The present investigation revisits the extracellular System R, now allowing for a finite production region of Dpp between the two chambers. It will be shown that this more refined model of the wing disc, designated as System F, leads to some qualitatively diferent morphogen gradient features. One significant diference between the two models is that System F impose no restriction on the morphogen production rate for the existence of a unique stable steady state concentration of the Dpp-receptor complexes. Analytical and numerical solutions will be obtained for special cases of System F. Some applications of the results for explaining available experimental data (to appear elsewhere) are briefly indicated. It will also be shown how the effects of the distributed source of System F may be aggregated to give an approximating point source model (designated as the aggregated source model or System A for short) that includes System R as a special case. System A will be analyzed in considerable detail in [6], and the limitation of System R as an approximation of System F will also be delineated there.

Chlamydia trachomatis is the most common cause of bacterial sexually transmitted infection. It produces an unusual intracellular infection in which a vegetative form, called the reticulate body (RB), replicates and then converts into an elementary body (EB), which is the infectious form. Here we use quantitative three-dimensional electron microscopy (3D EM) to show that C. trachomatis RBs divide by binary fission and undergo a sixfold reduction in size as the population expands. Conversion only occurs after at least six rounds of replication, and correlates with smaller RB size. These results suggest that RBs only convert into EBs below a size threshold, reached by repeatedly dividing before doubling in size. A stochastic mathematical model shows how replication-dependent RB size reduction produces delayed and asynchronous conversion, which are hallmarks of the Chlamydia developmental cycle. Our findings support a model in which RB size controls the timing of RB-to-EB conversion without the need for an external signal.