  During tissue development, patterns of gene expression determine the spatial
arrangement of cell types. In many cases, gradients of secreted signaling
molecules - morphogens - guide this process. The continuous positional
information provided by the gradient is converted into discrete cell types by
the downstream transcriptional network that responds to the morphogen. A
mechanism commonly used to implement a sharp transition between two adjacent
cell fates is the genetic toggle switch, composed of cross-repressing
transcriptional determinants. Previous analyses emphasize the steady state
output of these mechanisms. Here, we explore the dynamics of the toggle switch
and use exact numerical simulations of the kinetic reactions, the Chemical
Langevin Equation, and Minimum Action Path theory to establish a framework for
studying the effect of gene expression noise on patterning time and boundary
position. This provides insight into the time scale, gene expression
trajectories and directionality of stochastic switching events between cell
states. Taking gene expression noise into account predicts that the final
boundary position of a morphogen-induced toggle switch, although robust to
changes in the details of the noise, is distinct from that of the deterministic
system. Moreover, stochastic switching introduces differences in patterning
time along the morphogen gradient that result in a patterning wave propagating
away from the morphogen source. The velocity of this wave is influenced by
noise; the wave sharpens and slows as it advances and may never reach steady
state in a biologically relevant time. This could explain experimentally
observed dynamics of pattern formation. Together the analysis reveals the
importance of dynamical transients for understanding morphogen-driven
transcriptional networks and indicates that gene expression noise can
qualitatively alter developmental patterning.

Molecular Networks