Improved readout precision of the Bicoid morphogen gradient by early decoding

Abstract

Transcription factors (TFs) bind to specific DNA sequences to induce or repress gene expression. Expression levels can be tuned by changing TF concentrations, but the precision of such tuning is limited, since the fraction of time a TF occupies its binding site is subject to stochastic fluctuations. Bicoid (Bcd) is a TF that patterns the early Drosophila embryo by establishing an anterior-to-posterior concentration gradient and activating specific gene targets ("gap genes") in a concentration-dependent manner. Recently, the Bcd gradient and its in-vivo diffusion were quantified in live embryos, raising a quandary: the precision by which the Bcd target genes are defined (one-cell resolution) appeared to exceed the physical limits set by the stochastic binding of Bcd to DNA. We hypothesize that early readout of Bcd could account for the observed precision. Specifically, we consider the possibility that gap genes begin to be expressed earlier than typically measured experimentally, at a time when the distance between the nuclei is large. At this time, the difference in Bcd concentration between adjacent nuclei is large, enabling better tolerance for measurement imprecision. We show that such early decoding can indeed increase the accuracy of gap-gene expression, and that the initial pattern can be stabilized during subsequent divisions.

Spatiotemporal Analysis of Different Mechanisms for Interpreting Morphogen Gradients

“…For the r-model, s x is initially large and decreases to its steady-state value at large times. However, this behavior is not monotonic: at all positions the minimum error occurs at finite time (54). We find identical behavior for the r 0 -and _ r-models (Fig.…”

“…Although some progress can be made analytically (see the literature (22,53,54) and the Supporting Material), more accurate results are obtained by numerically solving for the altered boundary position (see the Supporting Material).…”

“…For example, there is increasing evidence that many morphogen gradients may actually be interpreted before steady state (22,(48)(49)(50)(51)(52). Theoretical work suggests that such pre-steady-state measurement may, in some circumstances, reduce the effects of fluctuations on the precision of spatial boundaries (22,53), particularly when coupled to a downstream gene network (54). Further, presteady-state readout could enable gene responses at different positions to be turned on at different times, providing much greater developmental flexibility.…”

Utilization of extracellular information before ligand-receptor binding reaches equilibrium expands and shifts the input dynamic range

“…During Drosophila melanogaster embryo development, before cellularization, the dividing nuclei decode the concentration of the morphogen Bicoid (start to express the Bicoid target gene Hunchback) before the Bicoid anteroposterior gradient reaches steady state. This process in known as "pre-steady-state decoding" (66,67).…”

Physical Limits on the Precision of Mitotic Spindle Positioning by Microtubule Pushing forces

“…The precision of this process is exemplified in the cycle-14 embryo by the hunchback protein, whose concentration profile varies from embryo to embryo by only 1%, less than one cell diameter [14] . It is argued that this high precision is at the very physical limit set by the diffusive movement and concentration fluctuations of the transcription factor that activates Hunchback [15,16] . Thus, the same physical limits to discrimination of chemical gradients by microorganisms [17] may also apply to chemical patterning of the body plan.…”