Modulation Of Adult Mammalian Neurogenesis By Sirtuin1 Proteins

Sumiti Saharan (2011). Modulation Of Adult Mammalian Neurogenesis By Sirtuin1 Proteins PhD Thesis, Queensland Brain Institute, The University of Queensland.

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Author Sumiti Saharan
Thesis Title Modulation Of Adult Mammalian Neurogenesis By Sirtuin1 Proteins
School, Centre or Institute Queensland Brain Institute
Institution The University of Queensland
Publication date 2011-03
Thesis type PhD Thesis
Supervisor Prof. Perry Bartlett
Dr. Dhanisha Jhaveri
Total pages 168
Total colour pages 27
Total black and white pages 141
Language eng
Subjects 11 Medical and Health Sciences
Abstract/Summary Adult neurogenesis is a multistage process regulated by a delicate balance between undifferentiated proliferative neural precursor cells and differentiated neurons. The differentiation of a neural precursor cell to a neuronal cell requires the silencing of self-renewal genes and the concurrent transcriptional activation of proneural genes. These precise changes in gene expression profile are orchestrated by epigenetic modulators such as histone deacetylases (HDACs). In this thesis, we have examined the role of a NAD+-dependent HDAC, Sirt1, in regulating neurogenesis within the two neurogenic niches of the adult brain, i.e. the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampus. The results presented in Chapter 3 demonstrate that cells in both these adult neurogenic niches express Sirt1. We further demonstrate that Sirt1 is highly expressed by proliferating neural precursors and is transcriptionally down-regulated during their differentiation. Having shown that Sirt1 is expressed by neural precursors, we next examine the effect of Resveratrol, an activator of Sirt1 enzymatic activity, on neural precursors in Chapter 4. The results presented in this chapter suggest a role for Sirt1 in regulating neural precursor activity and neurogenic potential. Chapter 5 details experiments conducted to directly manipulate Sirt1 protein levels within neural precursors in order to examine the regulatory effect of Sirt1 on their biology. Our results demonstrate that Sirt1 signalling does not affect the proliferative capacity of precursors but has a crucial and specific role in directing their neurogenic potential. Using the in vitro neurosphere differentiation assay, we demonstrate that enhancing Sirt1 signalling through Sirt1 overexpression blocks the neurogenic potential of adult neural precursors. In contrast, abrogation of Sirt1 signalling in proliferating precursors via RNA interference (RNAi) specifically directs them down a neuronal lineage. Furthermore, RNAi-mediated knockdown of Sirt1 in vivo is demonstrated to increase neuronal differentiation of neural precursors in the SGZ. Having ascribed a function for Sirt1 in relation to neural precursors, Chapter 6 examines the effects of genetic ablation of Sirt1 in neural precursors using conditional IX knockout transgenic mice. Analysis of the knockout mice reveals enhanced neurogenic potential of SGZ neural precursors within the hippocampus, resulting in increased neurogenesis. Furthermore, neural precursors derived from both the SVZ and SGZ, are shown to enhance neurogenesis in vitro, providing definitive evidence that Sirt1 signalling is an intrinsic mechanism that acts on neural precursors to inhibit their neurogenic potential. Finally, in Chapter 7 we examine the role of Sirt1 signalling on regulating neuronal survival. Our data suggest that the Sirt1 activator, Resveratrol, promotes survival of hippocampal neurons through a Sirt1-independent mechanism. Taken together, these findings elucidate a novel role of Sirt1 signalling in regulating the neurogenic potential of adult neural precursors and reveal Sirt1 to be a negative regulator of adult neurogenesis. The findings of this thesis are then discussed in light of the hypothesis that Sirt1 acts as an epigenetic checkpoint for neuronal differentiation, leading us to propose a mechanistic model to explain Sirt1 regulation of adult neural precursors.
Keyword neurogenesis, sirt1, hippocampus, subventricular zone, neural precursor, neurogenic potential
Additional Notes Color Pages: 23, 25, 27, 31, 33, 36, 43, 69-70, 76, 78-79, 81, 83-84, 90, 92-93, 95, 101-102, 111, 121, 127, 131-132, 141 Landscape: 102

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Created: Thu, 05 Jan 2012, 14:16:49 EST by Ms Sumiti Saharan on behalf of Library - Information Access Service