The adult mammalian brain is a highly plastic structure capable of cellular and molecular remodelling in response to its interactions with the outside world. The addition of new neurons to the hippocampus throughout life is one of the most striking manifestations of this plasticity. New neurons here are generated from a population of stem cells that, although existing primarily in a dormant or quiescent state, they can become activated upon the reception of neurogenic signals. How stem cells integrate these signals from the environment to ultimately control neuronal production is currently under investigation. During embryonic development, transcription factors of the basic helix-loop-helix family promote progenitor proliferation and differentiation to ensure the production of neurons in correct numbers and at the correct positions. We found Ascl1, a proneural factor in this family, to be expressed by stem cells of the adult hippocampus when in an active state. Here we used pharmacological and genetic approaches to show that Ascl1 expression is rapidly induced in response to neurogenic stimuli, and that deletion of this factor with a conditional inactivation approach results in an inability of stem cells to respond to signals and exit their quiescent state. Moreover, by examining the genes deregulated in Ascl1-deleted stem cells, we show that Ascl1 promotes the proliferation of hippocampal stem cells by directly regulating cell cycle regulatory genes, among which the cyclin D genes are of great importance. The data presented here supports a model whereby Ascl1 acts as a central factor in adult hippocampal stem cells to integrate both stimulatory and inhibitory signals and translate them into a transcriptional programme that controls stem cell activity. With this work we also highlight that understanding how Ascl1 is regulated will contribute, in the future, to the development of stem cell therapies for the treatment of neurological disorders.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:668510 |
| Date | January 2015 |
| Creators | Andersen, J. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1469969/ |
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