Modulation of the Hippocampal Neurogenic Program by the Circadian Clock Machinery and the small GTPase, Rasd1/ Dexras1

The mammalian hippocampal subgranular zone (SGZ) is home to a limited pool of quiescent neural stem/ progenitor cells (QNPs). These cells respond to intrinsic and extrinsic physiological changes, embark on the neurogenesis program and give rise to glutamatergic granule neurons that populate the dentate gyrus (DG). In this thesis, I uncovered two mediators of the neurogenic program: the circadian clock and the small GTPase, Dexras1. The circadian clock machinery controls daily timings in cellular events via the transcription-translation feedback loop (TTFL), which includes Bmal1 and Period2. In this thesis, I demonstrate the presence of the molecular clock and of rhythmic cell proliferation in the SGZ. The absence of Period2 abolishes the gating of cell cycle entrance of QNPs, whereas the genetic ablation of Bmal1 results in constitutively high levels of neurogenesis and cognitive defects. Mathematical model simulations show that the circadian clock may be essential in mediating cell-cycle inhibitors that targets the cyclin D/Cdk4-6 complex, and in turn disruptions in this system result in the abolishment of gating mechanisms. This study uncovers the interrelationship between the cell cycle and the circadian clock and emphasizes the importance of proper rhythmicity for hippocampal function. The most potent enhancer of hippocampal neurogenesis is physical exercise. The mechanism by which physical exercise promotes the rapid expansion of the proliferative pool remains elusive. Here, I demonstrate that exercise induces the cell cycle entrance of QNPs, a mechanism that is dependent on the presence of Dexras1. The loss of Dexras1 alters the survival of mitotic and post-mitotic cell survival in a stage-specific manner. At the molecular level, the absence of Dexras1 abolishes exercise-dependent activation of pro-mitogenic signaling cascades and inhibits the transcriptional up-regulation of neurotrophic factors. This study reveals Dexras1 as an important stage-specific regulator of exercise-induced neurogenesis in the adult hippocampus by enhancing pro-mitogenic signaling to neural progenitor cells and modulating cell survival. Altogether, this thesis demonstrates the high responsiveness of QNPs to extracellular signals. Within each chapter, I challenge current beliefs in the fields of circadian rhythms, cell signaling and neurogenesis, and develop new perspectives on adult stem cell regulation.

Department dc:contributor.department

Cell and Systems Biology

Year dc:date.issued

2018

Author dc:creator

• Bouchard Cannon, Pascale

Advisor dc:contributor.advisor

• Cheng, Hai-Ying Mary

• Cell cycle
• Circadian Clock
• Dexras1/ Rasd1
• Neurogenesis
• Stem Cell

Handle dc:identifier.uri

http://hdl.handle.net/1807/91835

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/91835