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Investigating Neural Stem and Progenitor Cell Intracrine Signaling Presented in Partial Fulfilment of the Requirements the Maste Investigating Neural Stem and Progenitor Cell Intracrine Signaling Presented in Partial Fulfilment of the Requirements the Master of Arts in the Psychology Graduate Program of The Ohio State University By Tyler Dause B.S. Graduate Program in Psychology Thesis Committee Elizabeth Kirby Ph.D., Advisor Kathryn Lenz Ph.D. Jonathan Godbout Ph.D. Copyrighted by Tyler Dause 2019 ii Abstract In the adult mammalian brain, there are two regions where neural stem and progenitor cells reside and proliferate throughout life: the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. While much of the current research focuses on these cells’ ability to create new neurons, a process known as neurogenesis, new findings indicate that neural stem and progenitor cells (NSPCs) may influence their niches through the secretion of growth factors. Our previous work indicates that NSPCs express 1/3 of the vascular endothelial growth factor (VEGF) in the DG. While global VEGF has been shown to support the proliferation and maturation of adult-born DG neurons, the role of NSPC-derived VEGF is not entirely understood. Our data suggest that VEGF plays a role in regulating NSPC stemness in the DG. Currently, we aim to investigate the role of a VEGF/VEGFR2 intracellular autocrine (i.e. intracrine) signaling pathway in regulating NSPC stemness and maintenance. This thesis contributes to our ongoing work by investigating the immediate effects of VEGF knockdown on NSPC stemness in vitro and modeling VEGF knockdown to determine the NSPC-derived VEGF signaling pathway in vivo. My results suggest NSPC-derived VEGF knockdown increases NSPC proliferation, which is indicative of impaired stemness, in vitro. To investigate VEGF intracrine signaling in vivo we utilized a transgenic mouse line of inducible NSPC-derived VEGF knockdown was accompanied by EYFP reporter expression. I investigated the possible limitations of this commonly used genetic model and discovered recombination induced expression of one fluorescent reported does not accurately predict recombination of another gene at a single cell level. These data indicate that we may not accurately identify NSPC-derived VEGF intracrine signaling using our mouse model. iii Acknowledgements I would like to thank Dr. Kirby for her encouragement, professional guidance and support of my thesis work. I would also like to thank the members of the Kirby lab, especially Mark Fongheiser and Armaan Cheema, for assistance with data collection. iv Vita Personal Information Graduate Education: The Ohio State University, Columbus, Ohio Field of Study: Psychology – Behavioral Neuroscience Advisor: Elizabeth Kirby Bachelor of Science (Magna Cum Laude) The Ohio State University, Columbus, Ohio Major: Behavioral/Systems Neuroscience with Research Distinction in Neuroscience GPA: 3.703 | Major GPA: 3.918 | Spring 2017 Publications Dause TJ, Kirby ED. (2019) Aging gracefully: social engagement joins exercise and enrichment as a key lifestyle factor in resistance to age-related cognitive decline. Neural Regeneration Research, 14, 39-42. Rieskamp, JD, Denninger, JK, Dause, TJ. (2018). “Identifying the Unique Role of Notch3 in Adult Neural Stem Cell Maintenance.” Journal of Neuroscience, 38, 3157- 3159. Fields of Study Major Field: Psychology v Table of Contents Abstract ................................................................................................................ iii Acknowledgments ................................................................................................ iv Vita ........................................................................................................................ v List of Tables ........................................................................................................ vi List of Figures ...................................................................................................... vii Introduction ............................................................................................................ 1 Methods ………………………………………………………………………………… 6 Results …………………………………………………………………………………. 11 Discussion ………………………………………………………………………………22 Future Directions………………………………………………………………………..27 Summary…………………………………………………………………………….…..28 Bibliography……………………………………………………………………………. 30 vi List of Tables Table 1: Primary and Secondary antibodies ………………………………………… 10 vii List of Figures Figure 1: Paracrine vs Autocrine vs Intracrine ………………………………… 4 Figure 2: Intracellular vs Extracellular VEGF …………………………………... 5 Figure 3: NSPC lentiviral Infection in vitro ……………………………………… 12 Figure 4: Lentiviral Infection in vivo …………………………………………..… 14 Figure 5: NSPC derived VEGF knockdown in vivo ...…….…………………… 16 Figure 6: EYFP and tdTomato Recombination in SVZ NSPCs …..…………..18 Figure 7: EYFP and tdTomato Overlap in SVZ NSPCs ..………….….......….. 19 Figure 8: EYFP and tdTomato Recombination in DG NSPCs ………….……..20 Figure 9: EYFP and tdTomato Overlap in DG NSPCs ………………………… 20 Figure 10: Representative EYFP+ and tdTomato+ NSPC subpopulations .... 21 viii Introduction Since the discovery of endogenous adult-born neurons in the 1960s suggested the possibility of adding functional neurons to the mature brain,1 the potential to use neural stem and progenitor cells (NSPCs) to produce new neurons in disease has garnered considerable attention. As our understanding of NSPC function in the brain develops, many scientists are investigating the use of stem cell therapies to combat a spectrum of neurological disorders. Usually, these therapies rely on the direct transplantation of exogenous stem cells or on targeting the endogenous population with different neurotrophic factors.1 Despite mixed success in rodents, clinical trials are pushing forward with stem cell-based therapy for a variety of neurodegenerative disorders. In many of these trials, the extracellular environment is manipulated to increase likelihood of success.1 For instance, in both endogenous1 and transplanted stem cell therapies1 exogenous extracellular growth factors are introduced to support stem cell engraftment, growth and survival. Therefore, it is critical to understand how, or even if, stem cells respond to these growth factors within the brain. There are two neurogenic niches in the adult mammalian brain where NSPCs reside and proliferate throughout life: the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. For years, the primary focus of NSPC research was neurogenesis, or the production of new neurons. In rodent models, numerous studies support the importance of adult-born neurons for proper hippocampal function, including learning and memory.2 However, recent findings suggest that neuronal differentiation may not be the only function of NSPCs. For example, NSPCs may also regulate the DG 1 microenvironment through the expression of growth factors.3 Indeed, NSPCs have been shown to be a significant source of vascular endothelial growth factor (VEGF) in the DG,3 though the role of this VEGF is not entirely understood. VEGF (also known as VEGFA) is expressed by neural precursors during development4 and NSPCs in the mature brain.3 In the developing embryo, VEGF expression from the neural tube is crucial for vasculogenesis, or the formation of the peri- neural vascular plexus.5 VEGF from neural precursors forms a chemotactic gradient, which attracts endothelial cells from the peri-neural vascular plexus and guides the ingression of sprouting vessels into the embryonic brain.6 Loss of just one VEGF allele in neural precursors is embryonic lethal due to improper cerebral vascularization as characterized by abnormal blood vessels7 and disrupted vessel patterning,4 underscoring the importance of neural precursor VEGF in development. Independent of brain vascularization, VEGF also supports the development of neurons and affects their structure,8 proliferation,9 and survival.10 In the adult brain, VEGF continues to play a role in angiogenesis, or the development of new blood vessels, particularly after injury.11 Similarly to development, VEGF also impacts the proliferation9 and survival of adult-born neurons.12 In most adult brain regions, astrocytes are the primary source of VEGF13 and in past studies of VEGF’s effects on NSPCs, this has been assumed to be the case in the neurogenic niches as well.9,14 However, my lab’s recently published data shows that NSPCs synthesize their own VEGF and despite the presence of VEGF from astrocytic populations, this self-derived VEGF is necessary to maintain their stemness.3 The mechanism by which NSPC-derived VEGF supports stemness is unknown. 2 While little is known about VEGF signaling in NSPCs, the intracellular signaling pathways of VEGF receptors are well-established in endothelial cells,15 hematopoietic stem cells16 and different forms of cancer cells.17–19 VEGF ligand binds to two related VEGF receptor tyrosine kinases, VEGFR1 (Flt1) and VEGFR2 (KDR).20 NSPCs are known to express VEGFR2.3 Based on findings in other cell types, VEGF binding to VEGFR2 leads to receptor dimerization,21 internalization,22 and the autophosphorylation of multiple tyrosine residues,23 specifically Y95124 and Y117525 in the intracellular domain. Phosphorylation of Y951 promotes PI3K activation and translocation of Akt to the membrane.23,24 Once at the membrane, Akt is phosphorylated, which triggers the activation of downstream signaling cascades and promotes cell survival.28 Independently, phosphorylation of Y1175 activates PLCγ.29 PLCγ initiates the phosphorylation of
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