eLife digest | Neural stem cell-encoded temporal patterning delineates an early window of malignant susceptibility in Drosophila
Some aggressive brain tumors that affect children start to form before the child is even born. These tumors often develop much more rapidly than tumors found in adults, and require fewer genetic mutations to become dangerous and invasive. However, it is not known why this happens.
Fruit flies are often used as animal models for cancer studies. As the fly brain develops, cells called neural stem cells divide several times, each time producing one stem cell and another cell known as the intermediate progenitor. The intermediate progenitor can itself divide one more time before maturing to become a neuron. Different types of neurons form in different stages of brain development. This is due to the sequential production of proteins called transcription factors in neural stem cells. Each transcription factor is inherited by a different set of intermediate progenitors and alters the activity of certain genes to determine the type of neuron the cells become.
Some genetic mutations can prevent intermediate progenitors from maturing and cause them to revert to a stem-cell-like state, which allows them to rapidly divide and form tumors. Here, Narbonne-Reveau, Lanet, Dillard et al. use fruit flies to investigate why tumors that form early on in development progress so rapidly. The experiments uncover a ‘molecular clock’ in the neural stem cells that marks out a window of time in which they generate intermediate progenitors that are prone to becoming cancerous. This clock is represented by the sequential production of transcription factors that, in addition to determining neuronal identity, also turn off various growth-promoting genes in cells as brain development proceeds. These genes sustain normal cell division, but are silenced later on to prevent cells from dividing too many times.
If the maturation of intermediate progenitors is disrupted early on in brain development while the growth-promoting genes are still active, the molecular clock fails to switch off the growth-promoting genes. As a result, these cells acquire an unlimited ability to divide, which drives tumor growth. However, later in development when the growth-promoting genes have already been switched off, disrupting the maturation of intermediate progenitors does not lead to these cells becoming cancerous.
Therefore, Narbonne-Reveau, Lanet, Dillard et al.’s findings explain why intermediate progenitors that mature early on in brain development are more prone to becoming cancerous than those that mature later, and why they need fewer mutations to become invasive. Most of the genes involved in this process are also found in humans. Therefore, the same mechanism might govern how aggressive childhood brain tumors are, which is a question for future studies to address.