|Cells becoming neurons (red) in mice lacking FOXO3. Image courtesy of Ashley Webb.|
Our grantee Anne Brunet at Stanford University has known for a while now that a protein called FOXO3 has something to do with longer lifespan in both lab animals and people. She and members of her lab also knew that FOXO3 is found in stem cells of the brain and seems to preserve those cells. What they didn’t know is how.
What the first author Ashley Webb discovered is that FOXO3 essentially counteracts a protein being studied by another of our grantees at Stanford–Marius Wernig. Wernig has shown that a protein called Ascl1 prompts cells to become neurons. Webb found that FOXO3 interferes with Ascl1, preventing the cells from becoming neurons and, in the case of neural stem cells, maintaining that critical pool of cells.
Stanford quoted Anne Brunet on their blog:
This was really exciting to us, because ASCL1 has been widely studied, in particular by Marius Wernig, MD, at Stanford, for its ability to convert or ‘reprogram’ cells into neurons. Ashley found that FOXO3 could inhibit the ability of ASCL1 to promote the expression of pro-neuronal genes and the formation of new neurons. This could explain how FOXO3 maintains the pool of adult neural stem cells: by preventing them from undergoing premature differentiation into neurons and by keeping them as “stem cells”.
Now, the question is whether FOXO3 is disrupted in brain diseases related to aging, like Alzheimer’s disease or dementia.
I should note that CIRM played two roles in the discovery of how FOXO3 functions, which was published in the July 25 issue of Cell Reports. One is that Brunet has a New Faculty Award from CIRM. The other is that the scientist who carried out much of this research, Ashley Webb, is married to a CIRM science officer (she doesn’t have CIRM funding).