In our latest PLOS Biology Roundup, we offer you a taste of the range of topics covered in our recently published articles, from how to prune the brain’s vasculature and drug discovery in yeast, to new insights into the internal workings of the body’s circadian clock.
Blood flow gets the brain’s vasculature into shape
The not inconsiderable activities of the vertebrate brain are supported by its vasculature – an elaborate network of blood vessels – that provide it with the oxygen and nutrients it needs. Because the architecture of this network is important for meeting the brain’s energy demands, and because disruptions to it can cause serious neurological problems, there is considerable interest in understanding how this vascular network develops.
During the early stages of brain vasculature formation, new brain blood vessels sprout off an existing vascular structure and then invade the brain. In a recent paper in PLOS Biology, Qi Chen and colleagues sought to understand how these early sprouts evolve into the elaborate blood vessel architecture that meets the brain’s energy needs. They investigated this process using the embryos of zebrafish, which are naturally transparent and develop outside of the mother’s body. Using transgenic zebrafish in which vascular endothelial cells are marked with fluorescent labels, they monitored changes in brain vasculature in the midbrain of live animals during the first few days of development. They observed that new blood vessel sprouts appear on day one post-fertilization, which transform into an intricate network of vessels by day two. As they carried on monitoring, they noticed over time that while vessel growth continued the degree of complexity and interconnectedness between vessels in the network decreased.
Why might this be? The authors hypothesized that the blood vessels that are pruned away may be redundant and that their pruning increases the efficiency of blood flow within the brain. Does blood flow itself contribute to this pruning process? Yes, say the authors: they show that the local blocking of blood flow triggers vessel pruning. They also show the mechanism by which pruning occurs – preferentially at loop-shaped vessel segments via the migration of endothelial cells to adjacent unpruned segments.
Together these findings show how hemodynamics contribute to a simpler, more efficient vasculature in better shape to meet the energy demands of the brain.
An evolutionary approach to drug discovery
One of the great insights to come from the Human Genome Project was the realization that evolution loves to conserve resources. Complexity in humans comes not from adding more and more genes, but from finding new ways to express them. Ancient gene modules used in new combinations pave the way for new traits. That’s why such distant relatives as yeast and humans share so many genes. And that’s why some researchers are taking an evolutionary approach to drug discovery.
The hope is that by identifying human disease genes (and their protein products) with counterparts in workhorse model organisms like yeast and mice, they can use the lab models to screen and test drug candidates for human disease. A new study published in PLOS Biology takes this approach to show that even though a given pathway serves different functions in yeast and humans, it might still prove a useful therapeutic target.
The pathway in the study helps maintain cell wall structure in plants and blood vessel formation (angiogenesis) in humans. The study shows that the fungicide thiabendazole, long used to control crop diseases, can also inhibit angiogenesis, an important factor in tumor growth and metastasis. This suggests that thiabendazole, already approved as safe for human use by the US Food and Drug Administration, might have therapeutic potential in treating cancer, a possibility to consider in future research.
In a comment on the paper, @eperlste points out that a pharmacological approach would have included other targets: “…there is already strong genetic and biochemical evidence demonstrating that benzimidazole family members can target at least tubulin, and, in the case of thiabendazole, potentially other targets given the high drug concentration required (250µM) to see anti-angiogenic effects.”
We encourage you to join the discussion on the paper by clicking on this link
Degrading the tick tock of the body clock
Circadian clocks are the means by which organisms adjust their physiology and behaviour to the daily cycle of day and night. Some of the internal workings of these clocks rely on molecular feedback loops that generate daily peaks and troughs (oscillations) in gene activity.
In the Drosophilafruit fly, two proteins called PERIOD (PER) and TIMELESS (TIM) coordinate the fly’s circadian clock– they accumulate during the night, form a complex, and then repress their own gene expression early in the morning. The temporal control of this
oscillation involves the degradation of the PER and TIM proteins by various means, including their being marked for destruction by phosphorylation and ubiquitination. One protein called SLMB is known to play a key role in controlling the degradation of phosphorylated PER and TIM. Now, Brigitte Grima and colleagues report - in a study recently published in PLOS Biology - that another protein called CUL-3 is also involved in the workings of this clock. These authors found that when they inhibited the activity of CUL-3, the oscillations of PER and TIM flattened out and the normal rest and activity rhythms of flies were abolished. This lead to their discovering that CUL-3 forms a complex with a lightly phosphorylated form of TIM when PER is not present; this complex allows this version of TIM to accumulate during the night. But when PER is present, SLMB preferentially interacts with this phosphorylated TIM, favoring its degradation.
From these findings the authors propose that CUL-3 and SLMB share the task of keeping the internal workings of this clock – the control of the oscillations of PER and TIM - in time with the day/night cycle.
If you’re interested in the workings of the circadian clock, you might also want to check out these other recently published PLOS Biology articles on this subject: