HHMI investigator Huda Y. Zoghbi and colleagues at Baylor College of Medicine prevented medulloblastoma from developing in mice by shutting down production of the protein Atoh1 in susceptible brain cells. The team's findings, reported in the December 4, 2009, issue of Science, suggest Atoh1 may be a new target for medulloblastoma treatment.
"When we cloned the gene for Atoh1 in 1996, we had no clue that it had any medical relevance," said Zoghbi, a neuroscientist and neurologist. "Now we know that it's critical for many medical issues, the most recent one being this common childhood cancer."
Atoh1 (also known as Math1) is a transcription factor that works in the nuclei of cells to keep certain genes switched on. It is evolutionarily ancient, appearing in slightly varying forms in various species, from fruit flies to humans. In cells where Atoh1 is active, it seems to be switched on only during fetal development, when cells proliferate rapidly to fill out the various parts of the nervous system.
However, in the region of the brain known as the cerebellum, Atoh1 is active after birth in the fast-dividing granule neuron precursor (GNPs) cells that eventually stop dividing and become mature granule neurons. "The cerebellar granule neurons are unique in that most of their development happens after birth, both in mice and humans," Zoghbi said.
A few years ago, experiments done in several laboratories hinted that Atoh1 might be required to keep GNPs in their fast-dividing state and make them more susceptible to developing into medulloblastoma tumors.
"The question for us was whether we could really prove, not just in the cell culture dish or in microarrays but in animals, that Atoh1 plays this role in medulloblastoma," Zoghbi said.
Ordinarily, to begin to discern the function of a gene such as Atoh1, researchers would engineer a strain of mice that lack the gene. But that had been tried in the 1990s, and the results were less than satisfying. Researchers found that Atoh1-knockout mice failed to develop properly in the womb, and died at birth. To study Atoh1's function after birth, Zoghbi's team, led by postdoctoral researcher Adriano Flora, devised a more advanced technique. First they bred a strain of mice with a genetic off-switch connected to their Atoh1 gene; then they injected a chemical into the brains of healthy newborn mice, to trigger this off-switch and eliminate the production of Atoh1 in GNPs. As a result, the GNPs immediately stopped proliferating and started maturing into granule neurons.
That result showed that Atoh1 helped keep GNPs in their ever-dividing state. Further experiments revealed that Atoh1 revs up GNPs by switching on a gene called Gli2, a well-known member of the Sonic Hedgehog signaling pathway that helps cells divide. The Sonic Hedgehog pathway is also inappropriately switched on in many cancers, including medulloblastoma.
"At this point we asked whether we could affect the development of medulloblastoma in mice by shutting down Atoh1," Zoghbi said.
To find out, the team applied their local Atoh1-shutdown technique to a special strain of mice with a specific genetic mutation that makes them develop medulloblastoma. In these mice, a mutant gene is switched on after birth, sending the Sonic Hedgehog signaling pathway into overdrive, causing precancerous lesions and tumors in the cerebellum. But when Zoghbi's team switched off Atoh1, these cancerous changes never occurred.
Establishing Atoh1 as a key player in the origin of medulloblastoma makes it a potential target for new drug treatments, Zoghbi said. But to Zoghbi, an important next step is to determine whether the protein is still needed to keep tumors growing after they've become established: "If we allow these tumors to develop, and then we take away Atoh1, would that make a difference?" Her lab and others are also now racing to determine what keeps Atoh1 inappropriately switched on in medulloblastoma cells, and what normally switches it off.
Zoghbi emphasized that she originally took up the study of Atoh1 as an exercise in pure biology, with no idea that it would have relevance to disease. "That just underscores the tremendous importance of doing science for science's sake," she said.
Jim Keeley | EurekAlert!
Make way for the mini flying machines
21.03.2018 | American Chemical Society
New 4-D printer could reshape the world we live in
21.03.2018 | American Chemical Society
In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.
Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...
Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.
They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...
A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...
For the first time, an interdisciplinary team from the University of Basel has succeeded in integrating artificial organelles into the cells of live zebrafish embryos. This innovative approach using artificial organelles as cellular implants offers new potential in treating a range of diseases, as the authors report in an article published in Nature Communications.
In the cells of higher organisms, organelles such as the nucleus or mitochondria perform a range of complex functions necessary for life. In the networks of...
Animal photoreceptors capture light with photopigments. Researchers from the University of Göttingen have now discovered that these photopigments fulfill an...
19.03.2018 | Event News
16.03.2018 | Event News
13.03.2018 | Event News
21.03.2018 | Physics and Astronomy
21.03.2018 | Materials Sciences
21.03.2018 | Life Sciences