Dynamic Maternal Gradients Control Timing and Shift-Rates for Drosophila Gap Gene Expression.

Berta Verd,Anton Crombach,Johannes Jaeger,David Umulis

doi:10.1371/journal.pcbi.1005285

Abstract

Pattern formation during development is a highly dynamic process. In spite of this, few experimental and modelling approaches take into account the explicit time-dependence of the rules governing regulatory systems. We address this problem by studying dynamic morphogen interpretation by the gap gene network in Drosophila melanogaster. Gap genes are involved in segment determination during early embryogenesis. They are activated by maternal morphogen gradients encoded by bicoid (bcd) and caudal (cad). These gradients decay at the same time-scale as the establishment of the antero-posterior gap gene pattern. We use a reverse-engineering approach, based on data-driven regulatory models called gene circuits, to isolate and characterise the explicitly time-dependent effects of changing morphogen concentrations on gap gene regulation. To achieve this, we simulate the system in the presence and absence of dynamic gradient decay. Comparison between these simulations reveals that maternal morphogen decay controls the timing and limits the rate of gap gene expression. In the anterior of the embyro, it affects peak expression and leads to the establishment of smooth spatial boundaries between gap domains. In the posterior of the embryo, it causes a progressive slow-down in the rate of gap domain shifts, which is necessary to correctly position domain boundaries and to stabilise the spatial gap gene expression pattern. We use a newly developed method for the analysis of transient dynamics in non-autonomous (time-variable) systems to understand the regulatory causes of these effects. By providing a rigorous mechanistic explanation for the role of maternal gradient decay in gap gene regulation, our study demonstrates that such analyses are feasible and reveal important aspects of dynamic gene regulation which would have been missed by a traditional steady-state approach. More generally, it highlights the importance of transient dynamics for understanding complex regulatory processes in development.

Highlights

These gradients are highly dynamic themselves, as they decay while being read out. We show that this decay controls the peak concentration of gap gene products, produces smooth boundaries of gene expression, and slows down the observed positional shifts of gap domains in the posterior of the embryo, thereby stabilising the spatial pattern
Our analysis demonstrates that the dynamics of gene regulation affect the timing, and the positioning of gene expression
We find that a monostable spiral sink drives gap domain shifts in the posterior of the embryo; this differs markedly from the unstable manifold observed in static-Bcd gap gene circuits [23]

Summary

Introduction

Like everything else that persists for more than an instant, there is a temporal dimension to their existence. What is less obvious is the active role that time plays in altering the rules governing biological processes. Many current attempts at understanding biological processes neglect important aspects of this temporal dimension [17]. Modelling studies frequently restrict themselves to a small-enough time window allowing them to ignore temporal changes in the rules governing the system. Often even necessary, such simplifications can lead us to miss important aspects of biological regulatory dynamics

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