Year: 2017
Type: dissertation
Abstract: In the adult mammalian brain, numerous complex regulatory networks exist in order to regulate adult neural precursor cell (NPC) maintenance throughout life. While many of these networks have been described, others remain less well understood. Here, we have asked about three of these pathways (specifically the p53 family, cellular senescence, and AMPK), using genetic and pharmacological tools to determine their roles in precursor maintenance and neurogenesis in vivo. First, we show that p53, p63, and p73 functionally interact in NPCs to regulate cell fate. When these interactions are perturbed due to combined p63;p73 heterozygosity, precursor pools and neurogenesis are rapidly depleted due to an increase in p53-mediated senescence. Second, we demonstrate that senescent NPCs rapidly accumulate in the subgranular zone (SGZ) with age, and this coincides with a decrease in neurogenesis and precursor numbers. When senescent cells in the SGZ are reduced either pharmacologically or genetically, neurogenesis and stem cell proliferation are dramatically enhanced, demonstrating a cell non-autonomous regulatory network between senescent and non-senescent precursors in the hippocampus. Last, we show that AMPK agonist metformin acts on two distinct pathways to regulate cell fate in adult neural precursors. Specifically, we demonstrate that metformin acts to enhance NPC proliferation and self-renewal via a TAp73-dependent mechanism. However, metformin can also promote NPC differentiation by activating an aPKC-CBP pathway, indicating that AMPK plays an important role in regulating cell fate decisions. Taken together, the results of this thesis demonstrate that complex regulatory networks including the p53 family, cellular senescence and AMPK act to maintain adult NPCs, and manipulation of these networks can drastically alter neurogenesis and precursor pools in vivo.
Source: TSpace (University of Toronto)
Author: Michael P. Fatt
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2782103158