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Hormonal Regulation of Neural Stem Cell Proliferation and Fate Determination

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Hormonal Regulation of Neural Stem Cell Proliferation and Fate Determination Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1394 Hormonal Regulation of Neural Stem Cell Proliferation and Fate Determination BY KARIN BRÄNNVALL ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2004 !!" !#$% & ' & & ( )* & +, - . ', / 0, !!", 1 2' & 3 4 ( & * , 5 , 6#", 6 , , 743 #8%%"8 8% 4 & & - & , 7 ' )34+ & - & ' & & & & -, 5 ' & )34+ & & , & - ' 34 & & , 7 & & ' ' - 98 ' )9841+ - : , 5 ' )258+ - - ' ' 34, ; & ' - ' && 34< 34 & ' , . ' = & - & & > , 7 ' - & ' && ' , 5 ? ? 6!@ 34 & ' ' & && 34 , 9841 ' ' & < 34 & - , * 258 - 34 & - ' && ' 258 34 >, 7 ' - & 34 ' - & & ' , 5 - & 9841 34 ' 258 34 >, 3 ( & * 1 5 ' ! " ! " # $! % &'(! ! )*(&+,- ! A 0 / !!" 7443 !B8C"C 743 #8%%"8 8% $ $$$ 8" #" ) $DD ,>,D E F $ $$$ 8" #"+ List of Papers I Brannvall, K., Korhonen, L., Lindholm, D. (2002). Estrogen- receptor-dependent regulation of neural stem cell proliferation and differentiation. Mol Cell. Neurosci. 21(3):512-20. II Brännvall, K.,* Korhonen, L.,* Skoglösa, Y., Lindholm, D. (2003). Tumor suppressor gene BRCA-1 is expressed by embryonic and adult neural stem cells and involved in cell proliferation J. Neurosci Res. 71(6):769-76. (*equal contribution). III Brännvall, K., Bogdanovic, N., Lindholm, D. 19-Nortestosterone Influences Neural Stem Cell Proliferation and Neurogenesis in the Rat Brain. Submitted to EJN IV Brännvall, K., Ingvarsson, H., Lindholm, D. D-MSH Dependent Regulation of Neural Stem Cell Proliferation. Manuscript. Reprints were made by permission from the publishers. Pictures on the cover: Embryonic neurospheres stained for: E-III-tubulin on the front page Nestin on the pack page All figures appearing in this thesis are made by Karin Brännvall Table of Contents INTRODUCTION ............................................................................................... 9 Stem Cells ....................................................................................................... 9 Totipotent, Multipotent and Pluripotent Stem Cells................................. 10 DifferentiatioDifferentiationn Potential of Somatic Stem Cells............... 11 Development of the Nervous System............................................................ 12 Formation of Brain and Spinal Cord ........................................................ 12 Neural Stem Cells..................................................................................... 13 The life of a Neural Stem Cell ...................................................................... 14 The Cell Cycle.......................................................................................... 15 Notch and Numb Pathway........................................................................ 16 Cell Fate Specific Transcription Factors: the bHLH Proteins.................. 17 Differentiation and Fate Determination.................................................... 18 Mature Cell Types within the Central Nervous System........................... 21 Hormones........................................................................................................... 24 Sex Hormones............................................................................................... 24 17E-Estradiol............................................................................................ 25 19-Nortestosterone ................................................................................... 28 The Melanocortin System ............................................................................. 29 Melanocortins in the Brain....................................................................... 30 BRCA-1 ........................................................................................................ 30 BRCA-1 Structure.................................................................................... 31 BRCA-1 Expression................................................................................. 31 BRCA-1 Mutant Mice.............................................................................. 32 Estrogen Dependent Regulation of BRCA-1 ........................................... 32 MATERIALS AND METHODS....................................................................... 33 Experimental Animals................................................................................... 33 Nandrolone/BrdU Injections ......................................................................... 33 Cell Culture................................................................................................... 33 Primary Neural Stem Cells....................................................................... 33 Cell Biology .................................................................................................. 34 Western blotting ....................................................................................... 34 Cell Proliferation...................................................................................... 34 Cell Differentiation .................................................................................. 35 Immunocytochemistry.............................................................................. 35 Immunohistochemistry............................................................................. 36 Stereology ................................................................................................ 37 Molecular Biology ........................................................................................ 39 RT-PCR.................................................................................................... 39 AIMS OF THE PRESENT INVESTIGATION................................................. 40 RESULTS AND DISCUSSION ........................................................................ 41 Estrogen Affects the Proliferation and Fate Determination of NSCs (PaperI) ....................................................................................................................... 41 BRCA-1 is localized to Proliferating Neural Precursors and Down Regulated upon Differentiation (Paper II)...................................................................... 41 19-Nortestosterone Influences Neural Stem Cell Proliferation and Neurogenesis in the Rat Brain (PaperIII)...................................................... 42 D-MSH is a Mitogen for Embryonic NSCs (Paper IV)................................. 42 GENERAL DISCUSSION AND FUTURE PERSPECTIVE ........................... 44 ACKNOWLEDGEMENT ................................................................................. 47 REFERENCES .................................................................................................. 49 ABBREVIATIONS AAS Anabolic Androgenic Steroids AF Activation Function D-MSH D-Melanocyte Stimulating Hormone apoE apolipoprotein E AR/ARs Androgen Receptor/Androgen Receptors ARKO Androgen Receptor Knock Out ArKO Aromatase Knock Out BERKO Estrogen Receptor E Knock Out bFGF basic Fibroblast Growth Factor bHLH basic Helix Loop Helix BMP/BMPs Bone Morphogenetic Protein/s BRCA Breast Cancer Susceptibility Gene BRCT BRCA-1 C-terminal repeat cAMP cyclic Adenosine Mono Phosphate cdc cell division control cdk cyclin dependent kinase CNP-ase 2´-3´-Cyclic Nucleotide-3´-Phosphodiesterase CNS Central Nervous System CNTF Ciliary Neurotrophic Factor DG Dentate gyrus DHT Dihydrotestosterone E Embryonic day EGF Epidermal Growth Factor ER/ERs Estrogen Receptor/Estrogen Receptors erk extra-cellular signal-related kinase ERKO Estrogen Receptor D Knock Out ES Cell Embryonic Stem Cell GFAP Glial Fibrillary Acidic Protein Hes Hairy and enhancer of split homolog HRT Hormone Replacement Therapy ICN Intra Cellular Notch Id Inhibitor of Differentiation LIF Leukemia Inhibitory Factor MAP kinase Mitogen activated kinase MCR Melanocortin receptor Ngn Neurogenin NR/NRs Nuclear Receptor/Nuclear Receptors NSC/NSCs Neural Stem Cell/Neural Stem Cells OB Olfactory Bulb P Post natal day PDGF Platelet Derived Growth Factor PI-3 kinase Phosphatidyl Inositol-3 kinase pRb Retinoblastoma protein RA Retinoic Acid RMS Rostral Migratory Stream Shh Sonic hedge hog SVZ Sub Ventricular Zone T3 tri-iodo-Thyronine INTRODUCTION Considering the difference in morphology and function of the cell types present in an adult organism, it is fascinating that they all have both the same genetic setup and also arise from one single cell, the fertilized egg: the first stem cell. This stem cell contains not only the blue print, but also the potential to form the entire offspring. Initially, the fertilized egg divides symmetrically, giving rise to daughter cells with interchangeable fate. Later during development, stem cells start to divide asymmetrically, giving rise to daughter cells with different fates. In the adult, only a small fraction of the total cell number will have maintained their stem cell potential. Since cells in organs such as the bone marrow are constantly replaced; cells with stem cell potential must reside in these tissues, even in the adult. Sur- prisingly, stem
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