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"IGF-II IS REQUIRED TO MAINTAIN NEURAL STEM CELLS ACROSS THE LIFESPAN"

by
Amber N. Ziegler
Integrative Neurosciences Program
B.S. 2006, Juniata College



Thesis Advisors: Steven W. Levison, Ph.D.
Teresa L. Wood, Ph.D.
Professors
Department of Neurology and Neurosciences

Thursday, November 15, 2012
10:30 A.M., Cancer Center G-1196


Abstract

The insulin-like growth factor (IGF) system plays a critical role in brain development and growth. Neural stem cells (NSCs), which are responsible for generating new brain cells throughout life, are located in two regions of the brain, the subventricular zone (SVZ) and the subgranular zone. The NSCs access various growth factors using small cilia that contact the cerebral spinal fluid. Whereas IGF-I is produced by neurons, IGF-II is highly abundant in the cerebral spinal fluid, however, it declines with age. IGF-I and IGF-II both activate the IGF-1R. In contrast, IGF-II, but not IGF-I activates a splice variant of the insulin receptor (IR) known as IR-A. We hypothesized that IGF-II would exert distinct effects on neural precursors than IGF-I, and that decreasing IGF-II in vivo would disrupt neurogenesis in the adult. Using multiple approaches, including the neurosphere assay, limiting dilution analysis, Q-PCR, flow cytometry and cell transplantation my studies show that IGF-II maintains and expands the population of NSCs in vitro. Within the SVZ I found that IGF-II is expressed along a medial-lateral gradient and using laser capture microdissection showed that the IGF-1R and the IR isoforms are also differentially expressed between the medial and lateral regions. These findings correlate with Q- PCR findings that IR-A is predominant in NSCs as opposed to lineage restricted cells. Next I perturbed IGF-II expression using C57BL/6J.CreERGt(ROSA)26Sor-igf2Fl/Fl mice. Tamoxifen was administered beginning at 1 month of age, which reduced IGF-II mRNA levels by 90%. Label-retaining cells were then assessed using two thymidine analogs (CldU and IdU). Two months after inducing igf2 gene deletion there were fewer label-retaining cells in the SVZ and subgranular zones. Correspondingly there were reduced numbers of Dcx+ immature neurons in the olfactory bulbs. Using an analysis of olfaction, mice lacking IGF-II were behaviorally impaired. Altogether these results support an essential role for IGF-II in NSC self-renewal both in vitro and in vivo in the young and aged mouse.


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