Modeling craniofacial development reveals spatiotemporal constraints on robust patterning of the mandibular arch

How does pattern formation occur accurately when confronted with tissue growth and stochastic fluctuations (noise) in gene expression? Dorso-ventral (D-V) patterning of the mandibular arch specifies upper versus lower jaw skeletal elements through a combination of Bone morphogenetic protein (Bmp), Endothelin-1 (Edn1), and Notch signaling, and this system is highly robust. We combine NanoString experiments of early D-V gene expression with live imaging of arch development in zebrafish to construct a computational model of the D-V mandibular patterning network. The model recapitulates published genetic perturbations in arch development. Patterning is most sensitive to changes in Bmp signaling, and the temporal order of gene expression modulates the response of the patterning network to noise. Thus, our integrated systems biology approach reveals non-intuitive features of the complex signaling system crucial for craniofacial development, including novel insights into roles of gene expression timing and stochasticity in signaling and gene regulation.Author summary: Proper development of the body requires boundaries to form between regions in which cells will form different structures, and these boundaries need to be properly organized in space. This must occur accurately even in moving, dividing cells and in the presence of the noise that is inherent in all biochemical processes. We use development of the upper and lower jaw as a model to study boundary formation. In this work, we combine detailed experimental measurements with computational modeling to investigate the role the timing of gene expression plays in organizing spatial boundaries, and find that the different orders of gene expression navigate a tradeoff between precision and accuracy in boundary positioning.