Diffusion makes gene expression patterns less diffuse

Embryonic development is driven by orderly, spatial patterns of gene regulatory proteins that assign each cell in the embryo its particular fate.

Recent experiments have shown that these patterns are highly precise, even though the synthesis of the gene regulatory proteins is very stochastic. Researchers from AMOLF and the John Innes Centre in England have developed a mathematical model that can resolve this paradox. Their model reveals that diffusion of the gene regulatory proteins is critical: diffusion can, surprisingly, enhance the precision of gene expression patterns.

All cells in our body contain the same set of genes, and yet not all cells are the same: a neuronal cell, for example, differs markedly from a liver cell. These differences arise because during embryonic development different sets of genes are turned on in the respective cells. This process of cell differentiation has to be orchestrated spatially, so that cells can form tissues and organs, which have well-defined structures. This is indeed the role of the spatial patterns of gene regulatory proteins: they ensure that the right genes are turned on in the right cells at the right place.

Cell differentiation is arguably best understood in the Bicoid-Hunchback system in the fruit fly Drosophila. Bicoid is a gene regulatory protein that forms an exponential gradient along the anterior-posterior axis of the embryo. One of the target genes of Bicoid is hunchback. This gene is activated when the Bicoid concentration is above some threshold, such that the concentration of Hunchback is high in the anterior half of the embryo and low in the posterior half. Recent experiments have shown that fluctuations in the positions where Hunchback crosses a threshold are very small, namely less than one cell. This means that the two halves of the embryo are very well defined. However, the mechanism underlying this sharp boundary was not understood: because the expression of hunchback is stochastic, it was expected that its gene expression boundary would be very diffuse.

Researchers from AMOLF and the John Innes Centre have developed a mathematical model that can quantitatively describe these experimental observations. Moreover, their model shows that diffusion of Hunchback itself is critical for generating a sharp expression boundary. Diffusion causes the Hunchback molecules that are produced in a burst of gene expression to be rapidly distributed over the neighbouring cells. Diffusion can thus enhance spatial patterns of proteins by washing out large fluctuations in their synthesis. The researchers believe that this mechanism, where diffusion can suppress biochemical noise, could also be exploited in other biological systems.

Reference: Role of Spatial Averaging in the Precision in Gene Expression Patterns, T. Erdmann, M. Howard and P. R. ten Wolde, Phys. Rev. Lett. 103, 258101 (2009), December 17, 2009.

For more information, please contact Prof. Dr. Pieter Rein ten Wolde 020-7547100

Figure: (A) Embryonic cell of the fruit fly Drosophila. Bicoid is coloured red and Hunchback green. (B) Average concentration profile of Bcd and a few instantaneous profiles of Hunchback. The arrows denote the width of the hunchback expression domain.