The SIRT1 deacetylase in neural stem cell function and oligodendrocyte generation in adults
Abstract/Contents
- Abstract
- While the adult mammalian brain has a relatively limited regenerative capacity, it does contain pools of neural stem and progenitor cells that can give rise to new neurons and glia. The mechanisms that govern the production of new neurons in the adult brain are beginning to be well understood, but much less is known about the production of other cell lineages, in particular oligodendrocytes, from adult neural stem cells. Given the importance of oligodendrocytes in myelination, how they are generated in the adult brain is a question of fundamental importance for both normal and pathological conditions. Here we show that loss of SIRT1, a deacetylase that is crucial for metabolism and neuroprotection, enhances the production of both neural stem cells and oligodendrocyte progenitor cells in the adult brain and in vitro. Conditional deletion of SIRT1 in adult neural stem cells reveals a cell-autonomous action of SIRT1 in the generation of glia in the niche surrounding the subventricular zone. We find evidence that SIRT1 loss may alter the pool of proliferating oligodendrocyte progenitor cells by controlling the PDGF receptor a (PDGFR a) signaling pathway. SIRT1 loss increases acetylation of lysine 9 of histone H3 at the Pdgfra gene locus, affecting Pdgfra expression and activation of downstream PI3K-Akt and p38 MAPK signaling pathways in adult neural stem and progenitor cells. The observation that a drug-targetable deacetylase and downstream signaling pathways impact oligodendrocyte expansion may facilitate the generation of oligodendrocytes for stem cell therapies to treat injury and demyelinating diseases.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2011 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Rafalski, Victoria Antonina |
|---|---|
| Associated with | Stanford University, Neurosciences Program. |
| Primary advisor | Brunet, Anne, 1972- |
| Thesis advisor | Brunet, Anne, 1972- |
| Thesis advisor | Andreasson, Katrin |
| Thesis advisor | Palmer, Theo |
| Thesis advisor | Rando, Thomas A |
| Advisor | Andreasson, Katrin |
| Advisor | Palmer, Theo |
| Advisor | Rando, Thomas A |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Victoria Antonina Rafalski. |
|---|---|
| Note | Submitted to the Program in Neuroscience. |
| Thesis | Ph. D. Stanford University 2011 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2011 by Victoria Antonina Rafalski
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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