Stem cells have the capacity for both self renewal, and to form all cell types in the body. Interestingly, so called neural stem cells (NSCs) are found in the adult human brain, which is of significance both out of a developmental perspective and from a clinical point of view. At the present moment, the regulation of neural stem cell (NSC) proliferation and fate determination is not completely understood.The overall aim of this thesis was to study the mechanisms that regulate NSC proliferation and fate determination in vitro and in vivo. In particular, the roles of the female sex hormone estrogen and the testosterone analogue nandrolone, as well as the melanocortin α-melanocyte stimulating hormone (α-MSH), were analyzed in this context. Also, the breast cancer susceptibility gene one (BRCA-1), was studied in the brain with emphasis on regions containing NSCs.Our findings show that estrogen and nandrolone have similar effects on NSCs; both decreased NSC proliferation and increased neurogenesis. Estrogen’s ability to reduce proliferation was due to increased levels of p21, an inhibitor of cyclin dependent kinases. In contrast, no change in p21 was observed in the case of nandrolone, indicating differential regulation. Adult rats subjected to nandrolone injections had 30% reduced NSC proliferation in the dentate gyrus, indicating profound effects on NSCs in vivo.The melanocortin α-MSH acted as a mitogen by increasing levels of cyclinD1 and retinoblastoma protein; as a result NSC proliferation was doubled…
Contents
INTRODUCTION
Stem Cells
Totipotent, Multipotent and Pluripotent Stem Cells
DifferentiatioDifferentiationn Potential of Somatic Stem Cells
Development of the Nervous System
Formation of Brain and Spinal Cord
Neural Stem Cells
The life of a Neural Stem Cell
The Cell Cycle
Notch and Numb Pathway
Cell Fate Specific Transcription Factors: the bHLH Proteins
Differentiation and Fate Determination
Mature Cell Types within the Central Nervous System
Hormones
Sex Hormones
17E-Estradiol
19-Nortestosterone
The Melanocortin System
Melanocortins in the Brain
BRCA-1
BRCA-1 Structure
BRCA-1 Expression
BRCA-1 Mutant Mice
Estrogen Dependent Regulation of BRCA-1
MATERIALS AND METHODS
Experimental Animals
Nandrolone/BrdU Injections
Cell Culture
Primary Neural Stem Cells
Cell Biology
Western blotting
Cell Proliferation
Cell Differentiation
Immunocytochemistry
Immunohistochemistry
Stereology
Molecular Biology
RT-PCR
AIMS OF THE PRESENT INVESTIGATION
RESULTS AND DISCUSSION
Estrogen Affects the Proliferation and Fate Determination of NSCs (PaperI)
BRCA-1 is localized to Proliferating Neural Precursors and Down Regulated
upon Differentiation (Paper II)
19-Nortestosterone Influences Neural Stem Cell Proliferation and Neurogenesis in the Rat Brain (PaperIII)
D-MSH is a Mitogen for Embryonic NSCs (Paper IV)
GENERAL DISCUSSION AND FUTURE PERSPECTIVE
ACKNOWLEDGEMENT
REFERENCES
Author: Brannvall, Karin
Source: Uppsala University Library
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