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A mosaic screen for genes regulating neural stem cell divisioins in the developing adult central nervous system of Drosophila

Final Activity Report Summary - NEURALSTEMSCREEN (A mosaic screen for genes regulating neural stem cell divisions in the developing adult central nervous system of Drosophila)

Neural stem cells generate all of the neurons in the adult brain during embryonic and fetal development. Studying how these stem cells divide to produce different types of neurons is critical for understanding how of human and animal brain size is regulated. It is also of fundamental importance for developing safe and efficient stem-cell based therapies for treating neurodegenerative diseases and brain injuries. More specifically, identifying the factors that trigger neural stem cells from starting and stopping to divide allows the accurate prediction of neuronal numbers generated by each treatment regime.

The fruitfly Drosophila shares app.75% of important genes with humans and its brain is also constructed from neural stem cell-like progenitor cells (called neuroblasts). Therefore, the sophisticated genetic techniques available in Drosophila provide a powerful way of modelling some aspects of mammalian brain growth and development. We conducted large-scale genetic screens of over 3000 Drosophila genes, searching for those that are necessary for the correct start and stop of neuroblast divisions. We found 16 genes that are required for neuroblasts to divide at the normal rate and 52 genes that instruct neuroblasts when to stop dividing. Interestingly, several genes appear to function by altering the structure of neuroblast chromatin, the material composed of DNA and proteins packaged into chromosomes.

In parallel to the genetic screen, we found that two proteins that bind to DNA (transcription factors), also regulate the time at which neuroblasts stop dividing, thereby influencing final brain size. Remarkably mutations in these two genes induce neuroblasts to continue dividing for much longer than normal, leading to new neurons being added to the adult brain. This study identifies a global mechanism for coordinating the number of neurons with the type of neurons generated by a neural stem cell.