Mutual Repression enhances the Steepness and Precision of Gene Expression Boundaries

Abstract

Embryonic development is driven by spatial patterns of gene expression that determine the fate of each cell in the embryo. While gene expression is often highly erratic, embryonic development is usually exceedingly precise. In particular, gene expression boundaries are robust not only against intrinsic noise from gene expression and protein diffusion, but also against embryo-to-embryo variations in the morphogen gradients, which provide positional information to the differentiating cells. How development is robust against intra- and inter-embryonic variations is not understood. A common motif in the gene regulation networks that control embryonic development is mutual repression between pairs of genes. To assess the role of mutual repression in the robust formation of gene expression patterns, we have performed large-scale stochastic simulations of a minimal model of two mutually repressing gap genes in Drosophila, hunchback (hb) and knirps (kni). Our model includes not only mutual repression between hb and kni, but also the stochastic and cooperative activation of hb by the anterior morphogen Bicoid (Bcd) and of kni by the posterior morphogen Caudal (Cad), as well as the diffusion of Hb and Kni. Our analysis reveals that mutual repression can markedly increase the steepness and precision of the gap gene expression boundaries. In contrast to spatial averaging and cooperative gene activation, mutual repression thus allows for gene-expression boundaries that are both steep and precise. Moreover, mutual repression dramatically enhances their robustness against embryo-to-embryo variations in the morphogen levels. Finally, our simulations reveal that gap protein diffusion plays a critical role not only in reducing the width of gap gene expression boundaries via spatial averaging, but also in repairing patterning errors that could arise due to the bistability induced by mutual repression.

29 pages, 9 figures, supporting text with 9 supporting figures; accepted for publication in PLoS Comp. Biol

References in corpus (5)

• Genetic Toggle Switch Without Cooperative Binding
• Fundamental Limits to Position Determination by Concentration Gradients
• The role of input noise in transcriptional regulation
• The role of spatial averaging in the precision of gene expression patterns
• Reaction coordinates for the flipping of genetic switches

Cited by in corpus (8)

• Intrinsic noise profoundly alters the dynamics and steady state of morphogen-controlled bistable genetic switches
• Statistical dynamics of spatial-order formation by communicating cells
• Extending the dynamic range of transcription factor action by translational regulation
• Stable developmental patterns of gene expression without morphogen gradients
• Stability of pattern formation in systems with dynamic source regions
• Spatial-Stochastic Simulation of Reaction-Diffusion Systems
• Precision of morphogen-driven tissue patterning during development is enhanced through contact-mediated cellular interactions
• Hunchback promoters can readout morphogenetic positional information in less than a minute