Helsinki University Biomedical Dissertations No. 119 FROM NEURAL STEM CELLS TO PRECURSORS - MOLECULAR REGULATION OF SELF-RENEWAL AND DIFFERENTIATION Katja Piltti Institute of Biomedicine Medical Biochemistry and Developmental Biology University of Helsinki and Department of Biological and Environmental Sciences Division of Physiology Faculty of Biosciences University of Helsinki ACADEMIC DISSERTATION To be publicly discussed with the permission of the Faculty of Biosciences, University of Helsinki, in Small Lecture Hall, Haartman Institute, Haartmanin katu 3, Helsinki on 24th of April 2009 at 12.00 p.m. Helsinki 2009 Thesis supervised by Thesis co-supervised by Kirsi Sainio, Docent Hannu Sariola, Prof. & Medical Biochemistry and Kirmo Wartiovaara, MD, PhD Developmental Biology Medical Biochemistry and Institute of Biomedicine, Developmental Biology University of Helsinki Institute of Biomedicine Finland University of Helsinki Finland Thesis committee members Tomi Mäkelä, Prof. Marjo Salminen, Docent Medical Biochemistry and Division of Biochemistry Developmental Biology Faculty of Veterinary Medicine Institute of Biomedicine University of Helsinki University of Helsinki Finland Finland Thesis reviewed by Ari Ristimäki, MD, Docent Juha Partanen, Docent Department of Pathology Developmental Biology Institute of Diagnostics Institute of Biotechnology University of Oulu University of Helsinki Oulu University Hospital Finland Genome-Scale Biology Research Program and Department of Pathology University of Helsinki Finland Opponent Custodian Jean-Léon Thomas, Juha Voipio, Prof. Research Director, PhD Department of Biological and Institute National de la Santé Environmental Sciences et de la Recherche Médicale (INSERM) Division of Physiology Faculté de Médecine Pitié Salpêtrière University of Helsinki Université Pierre & Marie Curie Finland Paris France ISBN 978-952-10-5454-9 (paperback) ISBN 978-952-10-5455-6 (PDF) ISSN 1457-8433 http://ethesis.helsinki.fi Yliopistopaino Helsinki 2009 From neural stem cells to precursors Table of Contents TABLE OF CONTENTS LIST OF ORIGINAL PUBLICATION ABSTRACT ABBREVIATIONS 1 REVIEW OF THE LITERATURE ........................................................................9 1.1 INTRODUCTION..............................................................................................9 1.2 NERVOUS SYSTEM DEVELOPMENT .........................................................10 1.2.1 Development of central nervous system (CNS) ..........................................10 Early events of the neural tube development ..................................................10 Molecular control of CNS patterning .............................................................11 1.2.2 Development of peripheral nervous system (PNS)......................................13 Neural crest....................................................................................................13 Sympathetic nervous system development .....................................................15 1.3 NEURAL STEM CELLS..................................................................................16 1.3.1 NSC niche..................................................................................................17 1.3.2 CNS stem cells and progenitors..................................................................17 Stem cells during CNS development..............................................................17 Stem cells in adult CNS .................................................................................18 1.3.3 PNS stem cells and progenitors..................................................................19 1.4 DIFFERENTIATION .......................................................................................20 1.4.1 NSC progeny in CNS.................................................................................20 Neurogenesis .................................................................................................20 Astrocyte differentiation ................................................................................21 Generation of oligodendrocytes......................................................................21 1.4.2 Differentiation of sympathetic lineage cells in PNS....................................22 1.5 SELF-RENEWAL............................................................................................23 1.5.1 Symmetric and asymmetric cell division ....................................................23 1.5.2 Control of NSC self-renewal......................................................................25 1.5.2.1 Transcription related factors................................................................25 Notch.............................................................................................................25 Numb.............................................................................................................25 Bmi-1 ............................................................................................................26 1.5.2.2 Cell cycle ............................................................................................26 Cyclin kinase inhibitors (CKIs)......................................................................27 Tumor suppressor p53....................................................................................28 Rb family proteins .........................................................................................29 Cytoskeleton, cytoskeletal tumor suppressor protein merlin and ERM protein ezrin...............................................................................................................30 1.6 CLASSICAL ONCOGENES............................................................................31 1.6.1 Human Papilloma Virus 16 E6/E7 oncogenes ............................................31 1.6.2 Myc -family...............................................................................................32 1.7 GROWTH AND SURVIVAL FACTORS OF GDNF AND VEGF-C-FAMILY …………………………………………………………………………………………34 GDNF family.................................................................................................34 GDNF family receptors..................................................................................34 From neural stem cells to precursors Table of Contents VEGF subfamily............................................................................................36 VEGF receptors.............................................................................................38 2 AIMS OF THE STUDY ........................................................................................40 3 MATERIALS AND METHODS...........................................................................41 4 RESULTS AND DISCUSSION.............................................................................44 4.1 Oncogenes and proto-oncogenes increase stem cell characteristics in CNS progenitors (I, II).......................................................................................................44 4.2 Tumor suppressors decrease both proliferation and self-renewal (I) ..................49 4.3 Cytoskeletal tumor suppressor NF2 protein merlin and ERM protein ezrin are restricted into different cell lineages during CNS development (III)...........................51 4.4 VEGF-C promotes cell proliferation and survival in developing sympathetic nervous system (IV) ..................................................................................................52 5 CONCLUDING REMARKS AND PERSPECTIVES .........................................55 6 ACKNOWLEDGEMENTS...................................................................................56 7 REFERENCES ......................................................................................................58 From neural stem cells to precursors Original Publications LIST OF ORIGINAL PUBLICATIONS This thesis is based on following original publications, which are referred to in text by their Roman numbers, and on some unpublished data. I Katja Piltti, Laura Kerosuo, Janne Hakanen, Minna Eriksson, Alexandre Angers- Loustau, Sirpa Leppä, Marjo Salminen, Hannu Sariola and Kirmo Wartiovaara E6/E7 ONCOGENES INCREASE AND TUMOR SUPPRESSORS DECREASE THE PROPORTION OF SELF-RENEWING NEURAL PROGENITOR CELLS Oncogene 10;25(35):4880-4889 (2006) II Laura Kerosuo, Katja Piltti, Heli Fox, Alexandre Angers-Loustau, Valtteri Häyry, Martin Eilers, Hannu Sariola and Kirmo Wartiovaara C-MYC INCREASES SELF-RENEWAL IN NEURAL PROGENITOR CELLS THROUGH MIZ-1. Journal of Cell Science 121:3941-3950 (2008) III Mikaela Grönholm, Tambet Teesalu, Jaana Tyynelä, Katja Piltti, Tom Böhling, Kirmo Wartiovaara, Antti Vaheri and Olli Carpen CHARACTERIZATION OF THE NF2 PROTEIN MERLIN AND THE ERM PROTEIN EZRIN IN HUMAN, RAT, AND MOUSE CENTRAL NERVOUS SYSTEM. Molecular and Cellular Neuroscience 28: 683-693 (2005) IV Katja Piltti, Anu Plaken, Paula Haiko, Fares Zeidán-Chuliá, Nina Perälä, Anna Popsueva, Madis Jakobson, Petri Auvinen, Marika J Karkkainen, Maria Herranen, Hannu Sariola, Kari Alitalo, Mart Saarma, Kirmo Wartiovaara and Kirsi Sainio VASCULAR ENDOTHELIAL GROWTH FACTOR C PROMOTES PROLIFERATION AND SURVIVAL OF EARLY SYMPATHETIC PROGENITORS. Submitted to Development From neural stem cells to precursors Abstract ABSTRACT Stem cells are responsible for tissue turnover throughout lifespan. Only highly controlled specific environment, “the stem cell niche”, can sustain undifferentiated stem cell-pool. The balance