Regulation and function of the stem cell activation factor Ascl1 in constitutive and injury-induced adult neurogenesis

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The purpose of this project is to understand why new nerve cells are produced only in particular areas of the brain and why injuries cannot be repaired in other brain areas. Nerve cells are produced by special cells called stem cells that retain the properties of cells in the embryo to divide and produce various types of specialized cells. Stem cells are only found in limited areas of the brain where they divide throughout life to produce new nerve cells. We have found a protein called Ascl1 that stimulates the divisions of the stem cells and is therefore important for the production of new nerve cells. Our collaborators at the Karolinska Institute in Sweden have also found that the same protein Ascl1 is also present after a stroke in another brain region and in a distinct type of cells called glial cells. Some of these glial cells behave like stem cells when Ascl1 is present after stroke, as they divide and produce new nerve cells, but others do not react to the presence of Ascl1 and fail to produce nerve cells. To help the brain repair the damages caused by strokes, there is clearly a need to improve how glial cells react to the injury and to help them become more like stem cells. For this, we need to understand better how Ascl1 works. With this project, we want first to understand why Ascl1 is present in stem cells and in some glial cells after a stroke but not in others. We will therefore study the molecules that control in which brain cells Ascl1 is found. Second, we want to understand why, when Ascl1 is present in glial cells, some behave like stem cells and divide while other do not react to the presence of Ascl1 and continue to behave like normal glial cells. Ascl1 is a transcription factor, which means that it controls the activity of many genes in the cells where it is present, and these genes in turn control the behavior of the cells such as their divisions. We will therefore examine the genes that are controlled by Ascl1 in stem cell-like glial cells that respond to Ascl1 and we will find out why the same genes are not controlled by Ascl1 in other glial cells.We expect our research to lead to a better understanding of how the brain reacts to injuries such as strokes and why it has a limited ability to replace the nerve cells lost with new cells. In the longer term, we hope to have learned enough of the effect of stroke on glial cells to help devise treatments that convert more glial cells into stem cells and help the brain repair itself.