Self-organized shuttling: generating sharp dorsoventral polarity in the early Drosophila embryo.

Morphogen gradients pattern tissues and organs during development. When morphogen production is spatially restricted, diffusion and degradation are sufficient to generate sharp concentration gradients. It is less clear how sharp gradients can arise within the source of a broadly expressed morphogen. A recent solution relies on localized production of an inhibitor outside the domain of morphogen production, which effectively redistributes (shuttles) and concentrates the morphogen within its expression domain. Here, we study how a sharp gradient is established without a localized inhibitor, focusing on early dorsoventral patterning of the Drosophila embryo, where an active ligand and its inhibitor are concomitantly generated in a broad ventral domain. Using theory and experiments, we show that a sharp Toll activation gradient is produced through "self-organized shuttling," which dynamically relocalizes inhibitor production to lateral regions, followed by inhibitor-dependent ventral shuttling of the activating ligand Spätzle. Shuttling may represent a general paradigm for patterning early embryos.

Creating gradients by morphogen shuttling.

Morphogen gradients are used to pattern a field of cells according to variations in the concentration of a signaling molecule. Typically, the morphogen emanates from a confined group of cells. During early embryogenesis, however, the ability to define a restricted source for morphogen production is limited. Thus, various early patterning systems rely on a broadly expressed morphogen that generates an activation gradient within its expression domain. Computational and experimental work has shed light on how a sharp and robust gradient can be established under those situations, leading to a mechanism termed 'morphogen shuttling'. This mechanism relies on an extracellular shuttling molecule that forms an inert, highly diffusible complex with the morphogen. Morphogen release from the complex following cleavage of the shuttling molecule by an extracellular protease leads to the accumulation of free ligand at the center of its expression domain and a graded activation of the developmental pathway that decreases significantly even within the morphogen-expression domain.

Students' Understanding of the Dynamic Nature of Genetics: Characterizing Undergraduates' Explanations for Interaction between Genetics and Environment.

The idea of the interaction between genes and environment in the formation of traits is an important component of genetic literacy, because it explains the plastic nature of phenotypes. However, most studies in genetics education characterize challenges in understanding and reasoning about genetic phenomena that do not involve modulation by the environment. Therefore, we do not know enough to inform the development of effective instructional materials that address the influences of environmental factors on genes and traits, that is, phenotypic plasticity. The current study explores college students' understanding of phenotypic plasticity. We interviewed biological sciences undergraduates who are at different stages of their undergraduate studies and asked them to explain several phenomena that involved phenotypic plasticity. Analysis of the interviews revealed two types of mechanistic accounts: one type described the interaction as involving the environment directly acting on a passive organism; while the other described the interaction as mediated by a sensing-and-responding mechanism. While both accounts are plausible, the second account is critical for reasoning about phenotypic plasticity. We also found that contextual features of the phenomena may affect the type of account generated. Based on these findings, we recommend focusing instruction on the ways in which organisms sense and respond.

Students' Conception of Genetic Phenomena and Its Effect on Their Ability to Understand the Underlying Mechanism.

Understanding genetic mechanisms affords the ability to provide causal explanations for genetic phenomena. These mechanisms are difficult to teach and learn. It has been shown that students sometimes conceive of genes as traits or as trait-bearing particles. We termed these "nonmechanistic" conceptions of genetic phenomena because they do not allow the space required for a mechanism to exist in the learner's mind. In this study, we investigated how ninth- and 12th-grade students' conceptions of genetic phenomena affect their ability to learn the underlying mechanisms. We found that ninth- and 12th-grade students with nonmechanistic conceptions are less successful at learning the mechanisms leading from gene to trait than students with mechanistic conceptions. Our results suggest that nonmechanistic conceptions of a phenomenon may create a barrier to learning the underlying mechanism. These findings suggest that an initial description of a phenomenon should hint at a mechanism even if the mechanism would be learned only later.

A WntD-Dependent Integral Feedback Loop Attenuates Variability in Drosophila Toll Signaling.

Patterning by morphogen gradients relies on the capacity to generate reproducible distribution profiles. Morphogen spread depends on kinetic parameters, including diffusion and degradation rates, which vary between embryos, raising the question of how variability is controlled. We examined this in the context of Toll-dependent dorsoventral (DV) patterning of the Drosophila embryo. We find that low embryo-to-embryo variability in DV patterning relies on wntD, a Toll-target gene expressed initially at the posterior pole. WntD protein is secreted and disperses in the extracellular milieu, associates with its receptor Frizzled4, and inhibits the Toll pathway by blocking the Toll extracellular domain. Mathematical modeling predicts that WntD accumulates until the Toll gradient narrows to its desired spread, and we support this feedback experimentally. This circuit exemplifies a broadly applicable induction-contraction mechanism, which reduces patterning variability through a restricted morphogen-dependent expression of a secreted diffusible inhibitor.