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Gdnf Family Receptors in Peripheral Target Innervation and Hormone Production

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Gdnf Family Receptors in Peripheral Target Innervation and Hormone Production GDNF FAMILY RECEPTORS IN PERIPHERAL TARGET INNERVATION AND HORMONE PRODUCTION Päivi Lindfors Neuroscience Center and Department of Biological and Environmental Sciences and Helsinki Graduate School in Biotechnology and Molecular Biology, Faculty of Biosciences, University of Helsinki Academic dissertation To be presented for public criticism, with the permission of the Faculty of Biosciences, University of Helsinki, in auditorium 1041 at Viikki Biocenter, on 1 September, 2006, at 12 noon. Helsinki 2006 1 Supervised by: Docent Matti Airaksinen Neuroscience Center University of Helsinki Finland Reviewed by: Docent Kirsi Sainio Institute of Biomedicine University of Helsinki Finland and Docent Juha Partanen Institute of Biotechnology University of Helsinki Finland Opponent: Professor Klaus Unsicker Institute for Anatomy and Cell Biology University of Heidelberg Germany ISBN 952-10-3309-6 (print) ISBN 952-10-3310-X (ethesis, pdf) Yliopistopaino, Helsinki 2006 2 To Mika 3 TABLE OF CONTENTS SELECTED ABBREVIATIONS ..................................................................................6 LIST OF ORIGINAL PUBLICATIONS.......................................................................7 ABSTRACT...................................................................................................................8 REVIEW OF THE LITERATURE ...............................................................................9 Introduction....................................................................................................................9 Glial cell line-derived neurotrophic factor family .........................................................9 GDNF family ligands.................................................................................................9 GDNF family receptors............................................................................................12 RET-dependent GDNF family signalling ................................................................14 RET-independent GDNF family signalling.............................................................18 Derivatives of the neural crest: peripheral nervous system and neuroendocrine cells 19 Somatic sensory nervous system .............................................................................20 Sympathetic nervous system and the adrenal gland ................................................24 Parasympathetic nervous system .............................................................................26 Enteric nervous system ............................................................................................27 Thyroid C-cells ........................................................................................................29 In vivo functions of GDNF family factors ...................................................................30 GDNF/GFRα1/Ret signalling in the development of the enteric and parasympathetic nervous systems............................................................................31 GDNF/GFRα1/Ret signalling outside the nervous system......................................32 NRTN/GFRα2 signalling in the development of the parasympathetic and enteric neurons.....................................................................................................................33 GFRα3/ARTN signalling in the migration and initial axon outgrowth of sympathetic neurons.................................................................................................34 PSPN may protect the brain from ischaemia ...........................................................35 RET mutations in human diseases ...........................................................................35 AIMS OF THE STUDY ..............................................................................................37 MATERIALS AND METHODS.................................................................................38 RESULTS AND DISCUSSION..................................................................................41 A. GFRα2 in peripheral neurons..................................................................................41 The development of intrapancreatic ganglia requires GFRα2.................................41 GFRα2 is needed to maintain the cell size of cholinergic sympathetic neurons .....42 GFRα2 is required to maintain the cell size of IB4-positive sensory neurons .........43 B. GFRα2 in peripheral innervation ............................................................................44 4 Reduced innervation of pancreas and small bowel in GFRα2-KO mice.................44 GFRα2 is required for sympathetic cholinergic target innervation .........................44 Reduced density of free nerve endings in GFRα2-KO mouse footpad epidermis...47 C. Phenotypes of GFRα2-deficient mice reflect the impaired target innervation .......49 Functional deficits contributing to growth retardation in GFRα2-KO mice ...........49 Reduced inflammatory pain response and enhanced thermal avoidance in GFRα2- deficient mice...........................................................................................................50 D. In vivo function of GFRα4 (IV) ..............................................................................54 Generation of GFRα4-KO mice...............................................................................54 GFRα4 and Ret are co-localized exclusively in the juvenile mouse thyroid gland.54 Normal development of thyroid C-cells in GFRα4-KO mice..................................55 Reduced thyroid calcitonin levels and increased bone formation rate in newborn and juvenile GFRα4-KO mice .................................................................................55 CONCLUSIONS..........................................................................................................58 ACKNOWLEDGEMENTS.........................................................................................59 REFERENCES ............................................................................................................60 5 SELECTED ABBREVIATIONS AChE acetylcholine esterase ARTN artemin BMP bone morphogenetic protein cAMP cyclic adenosine monophosphate CaR calcium-sensing receptor C-cells clear cells CGRP calcitonin gene-related peptide CNS central nervous system CT calcitonin DRG dorsal root ganglion E embryonic day ERK extracellular signal-regulated kinase GDNF glial cell line-derived neurotrophic factor GFL GDNF family ligand GFRα GDNF family receptor alpha GPI glycosyl phosphatidyl inositol HSCR Hirschsprung’s disease IB4 isolectin B4B KO knockout MAPK mitogen-activated protein kinase MEN2 multiple endocrine neoplasia type 2 mRNA messenger RNA MTC medullary thyroid carcinoma NCAM neural cell adhesion molecule NGF nerve growth factor NOS nitric oxide synthase NRTN neurturin NT-3 neurotrophin 3 P postnatal day P2X3 ATP gated cation selective channel 2X3 PCR polymerase chain reaction PGP9.5 protein gene product 9.5 PI3-K phosphatidylinositol 3-kinase PNS peripheral nervous system PSPN persephin RET Ret tyrosine kinase (rearranged during transfection) RT-PCR reverse transcription PCR SCG superior cervical ganglion SP substance P TGF-β transforming growth factor beta TH tyrosine hydroxylase TRP transient receptor potential Tyr Tyrosine VAChT vesicular acetylcholine transporter VIP vasoactive intestinal peptide WT wild-type 6 LIST OF ORIGINAL PUBLICATIONS This thesis is based on the following original articles, which are referred to in the text by Roman numerals (I-IV), as well as on some unpublished results. I Rossi J, Herzig K-H, Võikar V, Hiltunen PH, Segerstråle M, Airaksinen MS (2003) Alimentary tract innervation deficits and dysfunction in mice lacking GDNF family receptor α2. J Clin Invest 112(5): 707-716. II Hiltunen PH, Airaksinen MS (2004) Sympathetic cholinergic target innervation requires GDNF family receptor GFRα2. Mol Cell Neurosci 26: 450-457. III Lindfors PH, Võikar V, Rossi J, Airaksinen MS (2006) Deficient nonpeptidergic epidermis innervation and reduced inflammatory pain in glial cell line-derived neurotrophic factor family receptor α2 knock-out mice. J Neurosci 26(7): 1953-1960. IV Lindfors PH, Lindahl M, Rossi J, Saarma M, Airaksinen MS (2006) Ablation of persephin receptor glial cell line-derived neurotrophic factor family receptor α4 impairs thyroid calcitonin production in young mice. Endocrinology 147(5): 2237-2244. The original publications are reproduced with the permission of the copyright owner. Copyright © 2003 by the American Society for Clinical Investigation (I), Copyright © 2004 by Elsevier (II), Copyright © 2006 by the Society for Neuroscience (III), Copyright © 2006 by the Endocrine Society (IV). 7 ABSTRACT Glial cell line-derived neurotrophic factor (GDNF) family ligands: GDNF, neurturin (NRTN), persephin (PSPN) and artemin (ARTN), signal through a receptor complex consisting of a glycosyl phosphatidyl inositol (GPI)-linked subunit (GFRα1-4) and the transmembrane receptor tyrosine kinase Ret. The GDNF family factors can support the survival of various peripheral and central neuronal populations in vitro but are required in vivo, particularly for the development of the peripheral nervous system (PNS). GDNF has important functions also outside the nervous system, especially in kidney development. Activating mutations in the RET gene cause tumours in neuroendocrine cells, whereas inactivating mutations in RET are found in patients with Hirschsprung’s disease (HSCR) characterized
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