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Reconstructing life at its beginning, cell by cell

After 13 rapid divisions a fertilized fly egg consists of about 6,000 cells. They all look alike under the microscope. However, each cell of a Drosophila melanogaster embryo already knows by then whether it is destined to become a neuron or a muscle cell — or part of the gut, the head, or the tail. Now, Nikolaus Rajewsky’s and Robert Zinzen’s teams at the Berlin Institute of Medical Systems Biology (BIMSB) of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) have analyzed the unique gene expression profiles of thousands of single cells and reassembled the embryo from these data using a new spatial mapping algorithm. The result is a virtual fly embryo showing exactly which genes are active where at this point in time. “It is basically a transcriptomic blueprint of early development,” says Robert Zinzen, head of the Systems Biology of Neural Tissue Differentiation Lab. Their paper appears as a First Release in the online issue of Science.

“Only recently has it become possible to analyze genome-wide gene expression of individual cells at a large scale. Nikolaus recognized the potential of this technology very early on and established it in his lab,” says Zinzen. “He started to wonder whether — given a complex organized tissue — one would be able to compute genome-wide spatial gene expression patterns from single-cell transcriptome data alone.” BIMSB combines laboratories with different backgrounds and expertise, emphasizing the need of bringing computing power to biological problems. It turns out the institute had not only the perfect model system — the Drosophila embryo — to address Rajewsky’s question, but also the right people with the right expertise, from physics and mathematics to biochemistry and developmental biology.

“The virtual embryo is much more than merely a cell mapping exercise,” says Nikolaus Rajewsky, head of the Systems Biology of Gene Regulatory Elements Lab, who enjoyed returning to fly development 15 years after studying gene regulatory elements in Drosophilaembryos during his post-doctoral time at the Rockefeller University. Using the interactive Drosophila Virtual Expression eXplorer (DVEX) database, researchers can now look at any of about 8,000 expressed genes in each cell and ask, “Gene X, where are you expressed and at what level? What other genes are active at the same time and in the same cells?” It also works with the enigmatic long non-coding RNAs. “Instead of time-consuming imaging experiments, scientists can do virtual ones to identify new regulatory players and even get ideas for biological mechanisms,” says Rajewsky. “What would normally take years using standard approaches can now be done in a couple of hours.”

Breaking the synchronicity of the first cell divisions

In their paper, the MDC researchers describe a dozen new transcription factors and many more long non-coding RNAs that have never been studied before. Also, they propose an answer to a question that has puzzled scientists for 35 years: How does the embryo break synchronicity of cell divisions to develop more complex structures?

In a process called gastrulation, distinct germ layers form and cells become restricted with regard to which tissues and organs they may differentiate into. “We believe that the Hippo signaling pathway is at least partly responsible for setting up gastrulation,” says Rajewsky. The pathway controls organ size, cell cycles and cell proliferation, but had never been implicated in the development of the early embryo. “We not only showed that Hippo is active in the fly, but we could even predict in which regions of the embryo this would lead to a different onset of mitosis and therefore break synchronicity. And that is just one example for how useful our tool is to understand mechanisms that have escaped traditional science.”