Maintenance of somatic tissue functions necessitates stem cells to adaptively respond to physiological signals and differentiate while ensuring self-preservation through regulation of quiescence and self-renewal. Radial glia-like neural stem cells in the dentate gyrus subregion of the adult hippocampus give rise to dentate granule cells and astrocytes, a process referred to as adult hippocampal neurogenesis. Neural stem cells must balance long-term maintenance with demands for differentiation and expansion in response to distinct physiological signals. These fundamental decisions are governed by niche-signals that recruit cell-autonomous factors within adult hippocampal neural stem cells. Although a growing number of studies have begun to identify transcription factors that couple the regulation of adult hippocampal neural stem cell quiescence with asymmetric self-renewal, the identities of transcription factors that couple regulation of quiescence and symmetric self-renewal in the adult hippocampus (or adult brain) are largely not known. Here, we will test the central hypothesis that Kruppel-like factor 9 (Klf9), a zinc finger transcription factor, contributes to long-term maintenance and neural stem cell expansion in the adult hippocampus through regulation of quiescence and symmetric stem cell divisions. Towards this goal, we will build on our extensive preliminary data employing newly engineered conditional Klf9 knock out and mCherry knock-in fusion mice, population and clonal lineage tracing, and longitudinal live 2 photon imaging of individual adult hippocampal neural stem cells in vivo. Execution of the proposed Aims will establish a foundation for understanding how Klf9 levels in neural stem cells balance long-term preservation through regulation of quiescence with rapid mobilization and expansion through control of symmetric self-renewal in the adult brain. Insights gleaned from this proposal may guide strategies to replenish/expand the pool of neural stem cells and restore hippocampal circuit plasticity in different disease states, aging and following injury.
Identification of molecular mechanisms that mediate long-term preservation and expansion of adult neural stem cells may edify strategies to replenish the neural stem population and restore hippocampal circuit plasticity in different brain diseases, aging and following injury.
