| dc.description.abstract | The plasticity of the adult mammalian brain is determined by the number and proliferation capacity of neural stem cells (NSCs). The pool of NSCs responsible for populating the adult brain is established during prenatal development from a subset of embryonic NSCs that become temporarily quiescent. Despite understanding the importance of embryonic quiescence in forming the adult brain, the mechanisms driving regulation of and entry into quiescence are not known.
The mechanistic target of rapamycin (mTOR), a master regulator of cell size and growth, has been hypothesized to regulate the entry into or exit from quiescence in other stem cell populations, but has not been investigated in embryonic NSCs. Nor have the specific contributions of the two primary downstream effectors of mTOR, p-S6 and p-4EBP1, been robustly characterized throughout brain development.
This work found that these phosphorylation targets present independently, not coordinately, in embryonic neural progenitor cells, indicating their diverging contributions to cellular proliferation. The downstream phosphorylation targets of mTOR respond differentially to the induction of quiescence, suggesting activation of each target by the mTOR kinase may elicit distinct cellular functions. This work also revealed that embryonic and postnatal NSCs have differing responses to the induction of quiescence, including differences observed across diverse spatial populations.
Pharmacological inhibition of p-4EBP1, but not p-S6, was sufficient to induce quiescence in embryonic NSCs. However, multiple mTOR inhibitors failed to affect p-4EBP1 in neural stem cells, indicating a need for more specific and potent inhibitors of this effector. This work includes preliminary data to identify a p-4EBP1 specific inhibitor and a commentary on the potential therapeutic benefits such molecules may have. A clinical case demonstrating a unique response to the treatment of a pediatric brain tumor with mutation-specific treatments is also included and reflects the heterogenous signaling capacity of cells in disease.
Results from this project may inform treatments for diseases where NSC numbers and activity are known to be altered during pre- or postnatal development, including brain cancers and neurodegenerative disease, by highlighting specific effectors of mTOR as a drug target to stimulate or inhibit the expansion of NSCs. | |
