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Modulation of the Hippocampal Neurogenic Program by the Circadian Clock Machinery and the Small Gtpase, Rasd1/ Dexras1

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Modulation of the Hippocampal Neurogenic Program by the Circadian Clock Machinery and the Small Gtpase, Rasd1/ Dexras1 Modulation of the Hippocampal Neurogenic Program by the Circadian Clock Machinery and the small GTPase, Rasd1/ Dexras1 By Pascale Bouchard Cannon A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Cell and Systems Biology University of Toronto © Copyright by Pascale Bouchard Cannon (2018) Modulation of the Hippocampal Neurogenic Program by the Circadian Clock Machinery and the small GTPase, Rasd1/ Dexras1 Pascale Bouchard Cannon Doctor of Philosophy Department of Cell and Systems Biology University of Toronto 2018 Abstract 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. ii | P a g e 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. iii | P a g e Acknowledgements This thesis is the culmination of many years of around-the-clock work, which would not have been made possible without the assistance of an outstanding research group, the guidance from my supervisor, Prof Hai-Ying Mary Cheng and the never-ending support of my husband, Hilmi Johari. The production of these two research chapters hold special significance to me. The second chapter was submitted shortly before the birth of my first daughter, AnnaSophia and the third chapter was published following the birth of my second daughter, Eleanora. I hope this thesis inspires them to persevere in the pursuit of their passion and goals. I would also like to thank the many collaborators and friends that have supported my work throughout the years. iv | P a g e Table of Contents Acknowledgements .....................................................................................................................................................iv Table of Contents ......................................................................................................................................................... v List of Tables ...............................................................................................................................................................ix List of Figures .............................................................................................................................................................. x Chapter 1 – Introduction ............................................................................................................................................ 1 1.1 The Hippocampus............................................................................................................................................... 1 1.2 The Discovery of Hippocampal Neurogenesis................................................................................................... 3 1.3 Hippocampal Neurogenesis ............................................................................................................................... 4 Figure 1. Adult Hippocampal Neurogenesis ..................................................................................................... 7 1.4 Stage-specific Mediators of Adult Hippocampal Neurogenesis ........................................................................ 8 1.4.1 Quiescence .................................................................................................................................................. 8 1.4.1.1 Bone Morphogenic Protein (BMP) Signaling ................................................................................... 8 1.4.1.2 Notch Signaling ................................................................................................................................... 9 1.4.1.3 Gamma-Aminobutyric Acid (GABA) Signaling .............................................................................. 9 1.4.2 Proliferation ............................................................................................................................................. 10 1.4.2.1 The Cell Cycle of Amplifying Neural Progenitors (ANPs) ............................................................ 10 1.4.2.2 Cell Cycle Components and Neurogenesis ..................................................................................... 12 1.4.2.3 Sonic Hedgehog (Shh) Pathway ....................................................................................................... 13 1.4.2.4 Transcription Factors ....................................................................................................................... 14 1.4.3 Neuronal Fate Commitment ................................................................................................................... 15 1.4.3.1 Wnt/β-Catenin Pathway ................................................................................................................... 15 1.4.3.2 Transcription Factors ....................................................................................................................... 16 1.4.4. Neuronal Differentiation and Maturation ............................................................................................ 17 1.4.4.1 Gamma-Aminobutyric Acid (GABA) Signaling ............................................................................ 17 1.4.4.2 N-Methyl-D-Aspartic Acid (NMDA) Signaling .............................................................................. 18 1.4.4.3 Afferent Pathway Neurotransmitters and Neuropeptides. ........................................................... 19 1.4.4.4 Cyclin-dependent Kinase 5 .............................................................................................................. 21 1.4.4.5 Reelin ................................................................................................................................................. 22 1.5.1 Growth Factors ........................................................................................................................................ 24 1.5.2 Neurotrophins .......................................................................................................................................... 25 1.5.3 Cyclic AMP (cAMP)-Responsive Element Binding (CREB) protein. ................................................. 26 1.6 Programmed Cell Death ................................................................................................................................... 27 1.6.1 Apoptosis. .................................................................................................................................................. 27 1.6.2 Necrosis/ Necroptosis ............................................................................................................................... 28 1.6.3 Autophagy ................................................................................................................................................. 28 1.7 External Factors Influencing Hippocampal Neurogenesis ............................................................................ 29 1.7.1 Stress ......................................................................................................................................................... 29 1.7.2 Aging ........................................................................................................................................................
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