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Investigations Into the Role of Erbb4 in Mouse Development

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Investigations Into the Role of Erbb4 in Mouse Development Investigations into the role of ErbB4 in mouse development. Hester Tidcombe Supervisor: Martin Gassmann Submitted towards the degree of Doctor of Philosophy, University College London. - 1 - ProQuest Number: U643888 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest U643888 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Acknowledgements As countless people have said about many diverse undertakings, and more will no doubt say in the future: There are many people without whom this project would have been impossible. There are others without whom it would have been one heck of a lot easier... Many thanks to all the following, who all fall in the former category: John Atkinson, Amanda Barlow, Joe Brock, Jim Burt, Marion Caulfield, Elena Grigorieva, Ian Harragan, Frank Johnson, Stuart Law, Lesley McNeill, Kristine Cronhelm, Rod King, Tim Mohun, Dipa Natarajan, Randa Pember, Justin Peter, Melvyn Sherwood, Derek Stemple, Masa Tada, Paula Towers, Vicky Tsoni and Peter Woodhams. Particular thanks must go to Robb Krumlauf, my second supervisor, for his feedback. Also to Anita Mynett and Monica Dixon for their suggestions, help, and invaluable moral support, and to Monica for her meticulous proofreading. To Jon Golding, current acting supervisor, for endless patience and advice on both experiments and this thesis. And thanks to my primary supervisor, Martin Gassmann, for all his guidance and support over the last four years. Special thanks must go to David Franklin for everything, including financial support for the last year, providing dinner after late nights in the lab, and his unending encouragement and support. I promise never to embark on a PhD ever again! ACKNOWLEDGEMENTS............................................................................................................................2 ABSTRACT ................................................................................................................................................................................. 6 1. INTRODUCTION ............................................................................................................................................................... 7 1.1 Receptor ty r o sine k in a s e s ................................................................................................................................... 7 1.2 E r b B receptors a n d neuregulins ......................................................................................................................8 1.2.1 ErbB receptors ........................................................................................................................................................................................................... 8 1.2.2 Overview o f EGFR and the ErbB receptors .................................................................................................................................8 1.3 N e u r e g u l in s .................................................................................................................................................................13 1.3.1 Neuregulin-1 splice variants.................................................................................................................................................................... 13 1.3.2 Neuregplin structure.......................................................................................................................................................................................... 14 1.3.3 Other neuregulin-like proteins............................................................................................................................................................... 16 1.4 E r b B a n d n eu r eg u lin m u t a n t s ........................................................................................................................ 19 1.5 The H in d b r a in .............................................................................................................................................................19 1.6 The H ea rt a n d E r b B receptors a n d l ig a n d s ........................................................................................... 27 1.6.1 Heart trabeculation............................................................................................................................................................................................27 1.6.2 ErbB4 and the heart.......................................................................................................................................................................................... 28 1.6.3 ErbB3 and the heart.......................................................................................................................................................................................... 30 1.7 Ph eno ty pes of Er b B 2, Er b B3 a n d N RG k n o c k o u t s ............................................................................. 30 1.7.1 ErbB4 knockout neural phenotype..................................................................................................................................................... 34 1.8 Po ssible role of Er b B 4 in the h in d b r a in ....................................................................................................35 1.9 Re sc u e of the Er b B 4 -/- m o u s e ......................................................................................................................... 37 Figu re 1.1 Str uctu re of E r b B r e c e pt o r s ......................................................................................................... 39 Figu re 1.2 Str ucture of neuregulins ...................................................................................................................40 Figu re 1.3 L ig a n d b in d ing to Er b B r e c e pt o r s ................................................................................................ 41 Figu re 1.4 D ev elopm ent of the m o u se h in d b r a in ..........................................................................................42 Figure 1.5 Hypothetical E r b B 4 a ctiv ity m e c h a n ism .................................................................................43 2. MATERIALS AND METHODS ................................................................................................................................44 2.1 An im a l s .......................................................................................................................................................................... 44 2.1.1 Acquisition o f embryos ................................................................................................................................................................................... 44 2.2 G en o t y pin g ...................................................................................................................................................................45 2.2.1 Tail biopsies .............................................................................................................................................................................................................. 45 2.2.2 DNA isolation from tissue ...........................................................................................................................................................................45 2.3 PCR OF GENOMIC DNA ............................................................................................................................................. 46 2.3.1 ErbB4 alleles............................................................................................................................................................................................................ 46 2.4 Pla sm id su bclo n ing a n d transformation ................................................................................................ 49 2.4.1 HER4 plasmid......................................................................................................................................................................................................... 49 2.4.2 Isolation of cH4M2 plasmid ......................................................................................................................................................................51 2.4.3 Concentration and purity o f DNA...................................................................................................................................................... 51 2.4.4 Sequencing o f DNA........................................................................................................................................................................................... 51 2.4.5 Other plasmids ......................................................................................................................................................................................................
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