In vertebrate embryos, a gradient of the TGF-b morphogen Nodal directs cells to different germ layer fates. A long-standing question is what sets the shape of this pattern; how does the embryo control gradient length scale and rate of expansion? In this paper, we showed that Oep, a membrane-linked Nodal co-receptor protein, is potent regulator of Nodal ligand spread. Through quantitative modeling and analysis of signaling in oep-/- embryos, we discovered that continual Oep replacement is required for gradient stability. Without replacement, Nodal signaling activity propagates outward as a traveling wave. This work argues that the embryo’s strategy for replacement of cell surface receptors is a crucial—but underappreciated— determinant of pattern formation
This study demonstrates that stochastic switching between solitary and social lifestyles in B. subtilis arises from fluctuations in complex formation between a single transcriptional repressor and its antagonist. By constitutively expressing these two proteins in a heterologous host the stochastic state switching could be reconstituted in quantitative detail. This work identifies noisy complex formation as a novel mechanism for initiating cell fate decisions and multi-generational timing of commitments.
Developmental signals often drive the production of their own inhibitors. However, roles for negative feedback are difficult to clearly test as removal of inhibitors leads to hyperactive signaling. We demonstrated that feedback inhibition of Nodal signaling by its inhibitor Lefty is dispensable for normal zebrafish development: uniform exposure to a small molecule Nodal inhibitor could substitute for feedback in lefty mutants. Though not required for development per se, we found that Lefty feedback allows the embryo to correct perturbations to Nodal signaling. This work established the Nodal-Lefty system as an exciting model for robust developmental patterning.
Cells of the soil bacterium Bacillus subtilis can must choose between radically different lifestyles in exponential growth. Each cell can seek out new niches as a motile individual, or to cling to its progeny and found a sessile community. In these papers, we used a novel microfluidic device to capture and observe individual B. subtilis cells for hundreds of generations of growth in continually-replenished conditions. We found that the decision to found a multicellular community occurred in a purely stochastic fashion: each cell had the same probability of transitioning whether it had been solitary for one generation or a hundred. In contrast, commitment to the multicellular state was tightly timed, with communities always persisting for approximately 7 generations before synchronously disassembling. We went on to demonstrate that stochastic switching arises from fluctuations in complex formation between a single transcriptional repressor and its antagonist. Remarkably, constitutively expressing these two proteins in a heterologous host reconstituted the stochastic state switching in quantitative detail. This work establishes the B. subtilis unicellular-multicellular switch as an exciting and experimentally tractable model system for stochastic cell fate determination, and identified noisy complex formation as a novel kinetic mechanism for initiating cell fate decisions.