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A-Kinase Anchoring Proteins AKAP1, -4, -10 and -11 with Different Subcellular Localizations in Sertoli Cells and Their Roles in Male Fertility

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A-Kinase Anchoring Proteins AKAP1, -4, -10 and -11 with Different Subcellular Localizations in Sertoli Cells and Their Roles in Male Fertility A-kinase anchoring proteins AKAP1, -4, -10 and -11 with different subcellular localizations in Sertoli cells and their roles in male fertility Inaugural Dissertation submitted to the Faculty of Medicine in partial fulfillment of the requirements for the PhD-Degree of the Faculties of Veterinary Medicine and Medicine of the Justus Liebig University Giessen by M. Sc. Wang, Wenwen of Qingdao, China Gießen (2016) From the Institute for Anatomy and Cell Biology, Medical Cell Biology Director: Prof. Dr. med. Eveline Baumgart-Vogt of the Faculty of Medicine of the Justus Liebig University Giessen First Supervisor: Prof. Dr. med. Eveline Baumgart-Vogt Second Supervisor: Prof. Dr. habil. Christiane Herden Committee Members: Prof. Dr. Klaus-Dieter Schlüter, Prof. Dr. med. Eveline Baumgart-Vogt, Prof. Dr. habil. Christiane Herden Date of Doctoral Defense: 18th May 2016 II Declaration “I declare that I have completed this dissertation single-handedly without the unauthorized help of a second party and only with the assistance acknowledged therein. I have appropriately acknowledged and referenced all text passages that are derived literally from or are based on the content of published or unpublished work of others, and all information that relates to verbal communications. I have abided by the principles of good scientific conduct laid down in the charter of the Justus Liebig University of Giessen in carrying out the investigations described in the dissertation.” Wenwen Wang th Date: 18 May 2016 Place: Gießen, Germany III Contents 1 INTRODUCTION ............................................................................................................................ 7 1.1 THE WORLDWIDE SOCIAL PROBLEM OF INFERTILITY .............................................................................. 7 1.1.1 Cause of male infertility ............................................................................................................. 7 1.2 SERTOLI CELLS ............................................................................................................................................... 8 1.2.1 Morphology and function of Sertoli cells ............................................................................. 8 1.2.2 Models to study Sertoli cells in vitro ................................................................................... 10 1.2.3 Sertoli cell function regulation ............................................................................................. 10 1.3 AKAPS: SCAFFOLDS FOR LOCAL SIGNALING .......................................................................................... 13 1.3.1 AKAP binding features and signaling cross-talk ........................................................... 14 1.3.2 Structure of AKAP-PKA interaction .................................................................................... 15 1.3.3 Diversity and evolution within the AKAP family ........................................................... 17 1.4 A CLOSER LOOK TO FOUR AKAPS USED IN THIS STUDY ....................................................................... 18 1.4.1 AKAP11 (=AKAP220)................................................................................................................ 18 1.4.2 AKAP1 ............................................................................................................................................. 21 1.4.3 AKAP4 ............................................................................................................................................. 28 1.4.4 AKAP10 .......................................................................................................................................... 29 1.5 THE FUNCTION OF AKAP1, AKAP4, AKAP10 AND AKAP11 IN GENITAL ORGANS ................... 30 1.5.1 Steroid hormone biosynthesis ............................................................................................... 30 1.5.2 Sperm development .................................................................................................................. 31 1.5.3 Oocyte maturation .................................................................................................................... 31 1.5.4 Prostate cancer ........................................................................................................................... 32 1.6 PEROXISOMES AND INFERTILITY ............................................................................................................. 32 1.6.1 Metabolic pathways in peroxisomes involved in male fertility ................................ 32 1.6.2 Peroxisomal matrix protein translocation and import machinery ........................ 34 1.7 AIMS OF THE THESIS .................................................................................................................................. 35 2 MATERIALS .................................................................................................................................. 36 2.1 CELL LINE AND MEDIUM ............................................................................................................................ 36 2.2 ROUTINE MATERIALS ................................................................................................................................ 36 2.3 BUFFER RECIPES ......................................................................................................................................... 39 2.4 AKAP PLASMIDS ........................................................................................................................................ 40 2.5 PRIMERS ...................................................................................................................................................... 42 2.6 ANTIBODY LIST ........................................................................................................................................... 47 3 METHODS ..................................................................................................................................... 49 3.1 BIOINFOMATIC SCREENING FOR THE AKAPS WITH PUTATIVE PTS1 SIGNALS ............................... 49 3.1.1 Scan of AKAP sequences for the consensus PTS1 motif .............................................. 49 3.1.2 Use of ClustalX 2.0 & MEGA 4.0.2 programs to create an evolutionary tree ...... 49 Page | 4 3.1.3 Use of Python 2.7.5 & R i386 3.0.1 programs to test AKAP1, AKAP4, AKAP10 through PTS1 predictor .............................................................................................................................................. 50 3.2 CELL CULTURE ............................................................................................................................................ 52 3.2.1 Cell culture routine ................................................................................................................... 52 3.2.2 Cell number and viability examination ............................................................................. 52 3.2.3 Isolation of total RNA from TM4 cells ................................................................................ 53 3.3 RT-PCR ...................................................................................................................................................... 53 3.4 SDS-PAGE AND WESTERN BLOTS ......................................................................................................... 54 3.5 PEROXISOME PURIFICATION BY OPTIPREP™ DENSITY GRADIENT CENTRIFUGATION ..................... 54 3.6 RAT DISSECTION AND RNA ISOLATION .................................................................................................. 59 3.6.1 Anaesthesia for rats and dissection of different organs ............................................. 59 3.6.2 Tissue total RNA isolation ...................................................................................................... 59 3.6.3 Ethanol precipitation to concentrate total RNA ........................................................... 60 3.7 WORKFLOW FOR NORTHERN BLOTTING ................................................................................................ 60 3.7.1 Plasmid construction and probe generation by in vitro RNA transcription ...... 62 3.7.2 Dot blot assay for detection of DIG-labeling efficiency ............................................... 62 3.7.3 RNA samples and agarose gel preparation ..................................................................... 63 3.7.4 Protocol of Northern blotting ............................................................................................... 63 3.8 CONSTRUCTION OF MYC-TAGGED AKAP PLASMIDS AND EXPRESSION IN TM4 CELLS ................... 64 3.8.1 Construction of myc-tagged AKAPs and GFP plasmids ............................................... 65 3.8.2 Procedures for bacterial transformation ......................................................................... 68 3.8.3 Point mutation assay ................................................................................................................ 70 3.8.4 Coating cover slips with poly-L-lysine ............................................................................... 71 3.8.5 Transient transfection of TM4 cells .................................................................................... 72 3.8.6 Immunofluorescence protocol .............................................................................................
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