In time we trust: how precise temporal regulation of the genome is essential for fruit fly embryogenesis

Looking at old questions with today’s eyes

The tiny fruit fly Drosophila melanogaster has been one of geneticists’ favourite models to understand the foundations of embryonic development. Decades of ground-breaking work led to the discovery of a panoply of hierarchically organized genes that transform a mass of undifferentiated cells into a highly organized embryo. This rock-solid foundation of knowledge, combined with other recent technical innovations unique to the fly, makes it a powerful model system to dissect basic questions about how genomes are regulated. Jacques Bothma and his team decided to revisit some of these well-established models of embryonic development. Using state-of-the-art single-cell live imaging tools, they explored the regulation of the Fushi tarazu (Ftz) gene. This gene encodes a transcription factor that controls important cell fate decisions. Ftz is initially present throughout the entire fly embryo but over the course of an hour it becomes restricted to a series of asymmetric stripes (see video below). But how does this happen? Well, that was the question the team aimed to answer in the present study.

Ftz expression dynamics in early Drosophila embryo (image size: 118 microns)

Same enhancers, different regulation

It was known that Ftz expression is regulated by two enhancers. Enhancers are regions of DNA that contain binding sites for transcription factors and other proteins and control expression of individual genes. In the prevailing model, one of these enhancers, named zebra, is first triggered to produce rough graded bands of Ftz protein. Next, the activation of the second enhancer, called autoregulatory, uses positive feedback to determine which cells will have high or low levels of Ftz, defining the sharp boundaries of the stripes. Anthony Birnie, co-first author of the study says: “We did not discover new enhancers but we visualized their activity in real time for the first time”. The results could not have been more surprising. As it turns out, zebra is the enhancer driving the decision of which cells will be at the boundaries of the stripes, while the job of autoregulatory is solely to perpetuate this decision.

Timing is everything

Ftz itself binds to the autoregulatory enhancer and is involved in activating it. In the prevailing model, the autoregulatory enhancer is activated when the Ftz protein concentration reaches a certain level. However, the researchers observed that this enhancer was activated almost simultaneously across the different stripes, even if these stripes were formed at different times. A closer look at the data revealed that, contrary to what was previously thought, the activation of this enhancer occurs in a time-dependent manner. “For me this ‘timer mechanism’ was completely unexpected,” says Bothma, “I initiated the project based on the prevailing model, hoping to build on it to study random cell fate switching in vivo, but the data took us down a very different path which ultimately ended up being more interesting”. The findings lead the authors to postulate a paradigm shift from the prevailing model, towards a new model where time-dependent regulation of gene expression may be a general mechanism for ensuring that embryogenesis runs like clockwork.

Publication

Precisely timed regulation of enhancer activity defines the binary expression pattern of Fushi tarazu in the Drosophila embryo. Anthony Birnie, Audrey Plat, Cemil Korkmaz, Jacques P. Bothma. Current Biology, 2023.

This news item was written by Euclides Fernandes Póvoa.