Final Report Summary - NEUROSYSTEM (A Systems Level Approach to Proliferation and Differentiation Control in Neural Stem Cell Lineages)
Although neuroblasts divide perpetually during development, they eventually disappear. This process of stem cell differentiation also occurs in our own brain where defects in cell cycle exit can lead to the formation of child tumors. We could identify the mechanism that is responsible for the timely stop in neuroblast division. Much to our surprise, we found that a change in how neuroblasts deal with nutrients is responsible for this. Normally, sugars like glucose are converted to other products that in turn can be used to build cellular components required for growth. At a certain time in development, however, a hormonal signal tells the cell to burn the sugars into carbon dioxide instead. This is called aerobic metabolism as it uses Oxygen and occurs in specialized organelles called mitochondria. We could show that this switch in metabolism is the key event that ends neuroblast divisions as it deprives cells of their building blocks for growth. As a consequence, they reduce their volume with each division until they are too small to divide and form specialized neurons.
Ultimately, we want to apply our findings from fruit flies to the human brain. This is difficult as experiments in humans are impossible and experiments in highly developed animals are ethically problematic. To develop an alternative strategy, we have developed a 3-dimensional cell culture method where we build human brain tissue starting from pluripotent stem cells. Our method can recapitulate the first few weeks of human brain development in an incubator with remarkable precision. The human cortex, the largest and most complex area of our brain, is recapitulated particularly well. As we can start the culture with stem cells originating from any human individual, we can recapitulate individual brain formation and neurological disease. We have used stem cells from a patient suffering from a severe brain disorder named microcephaly where brain volume and number of neurons is dramatically reduced, We were able to recapitulate those defects in our culture model and could identify a potential mechanism that may be the root cause for this disease. Our model has enormous potential, not only for transferring our results from fruitflies to humans but also for generating culture models for major human brain disorders allowing drugs and chemicals to be tested in human tissue directly without the need for animal models.