Mathematical and In Silico Analysis of Synthetic Inhibitory Circuits That Program Self-Organizing Multicellular Structures

Bottom-up approaches are becoming
increasingly popular for studying
multicellular self-organization and development. In contrast to the
classic top-down approach, where parts of the organization/developmental
process are broken to understand the process, the goal is to build
the process to understand it. For example, synthetic circuits have
been built to understand how cell–cell communication and differential
adhesion can drive multicellular development. The majority of current
bottom-up efforts focus on using activatory circuits to engineer and
understand development, but efforts with inhibitory circuits have
been minimal. Yet, inhibitory circuits are ubiquitous and vital to
native developmental processes. Thus, inhibitory circuits are a crucial
yet poorly studied facet of bottom-up multicellular development. To
demonstrate the potential of inhibitory circuits for building and
developing multicellular structures, several synthetic inhibitory
circuits that combine engineered cell–cell communication and
differential adhesion were designed, and then examined for synthetic
development capability using a previously validated in silico framework.
These designed inhibitory circuits can build a variety of patterned,
self-organized structures and even morphological oscillations. These
results support that inhibitory circuits can be powerful tools for
building, studying, and understanding developmental processes.