Stable developmental patterns of gene expression without morphogen gradients

Abstract

Gene expression patterns (GEPs) are established by cross-regulating target genes that interpret morphogen gradients. However, as development progresses, morphogen activity is reduced, leaving the emergent GEP without stabilizing positional cues. The GEP then can be deteriorated by the intrinsically noisy biochemical processes acting at the cellular level. However, the established GEPs remain spatio-temporally stable in many biological systems. Here we combine spatial-stochastic simulations with an enhanced sampling method (Non-Stationary Forward Flux Sampling) and a recently developed stability theory to address how spatiotemporal integrity of a GEP is maintained without morphogen gradients. Using a minimal embryo model consisting of spatially coupled biochemical reactor volumes, we study a stripe pattern in which weak cross-repression between nearest neighbor domians alternates with strong repression between next-nearest neighbor domains, inspired by the gap gene system in the Drosophila embryo. We find that fine-tuning of the weak repressive interactions to an optimal level increases temporal stability of GEPs by orders of magnitude, providing stability over developmentally relevant times, without morphogen gradients. The numerically determined optimal parameter regime closely agrees with the predictions of the stability theory. By analizing the dynamics of GEP asymmetry factors, we trace back the pattern stability enhancement to the emergence of a metastable basin and restoring forces that counteract pattern perturbations. The origin of these forces is further explained by the effective model, describing the emergent deterministic dynamics of the system. Altogether, we show that metastable attractors can emerge as a property of stochastic GEPs even without system-wide positional cues, provided that the gene regulatory interactions shaping the pattern are optimally tuned.