Schering Foundation Workshop 6

Transgenic Animals as Model Systems for Human Diseases

Schering Foundation Workshop

Editors: Gunter Stock Ursula-F. Habenicht

Vol. 1 Bioscience ~ Society Workshop Report Editors: D. J. Roy, B. E. Wynne, R. W. Old

Vol. 2 Round Table Discussion on Bioscience ~ Society Editor: J. J. Cherfas

Vol. 3 Excitatory Amino Acids and Second Messenger Systems Editors: V. I. Teichberg, L. Turski

Vol. 4 Spermatogenesis - Fertilization - Contraception Editors: E. Nieschlag, U.-F. Habenicht

Vol. 5 Sex Steroids and the Cardiovascular System Editors: P. Ramwell, G. Rubanyi, E. Schillinger

Vol. 6 Transgenic Animals as Model Systems for Human Diseases Editors: E. F. Wagner, F. Theuring

Schering Foundation Workshop 6

Transgenic Animals as Model Systems for Human Diseases E. F. Wagner, F. Theuring, Editors

With 39 Figures

Springer-Verlag Berlin Heidelberg GmbH

ISBN 978-3-662-02927-5 ISBN 978-3-662-02925-1 (eBook) DOI 10.1007/978-3-662-02925-1

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Preface

In late 1980, the first paper describing the introduction of cloned DNA into fertilized mouse eggs by microinjection was published. During the next few months, several groups reported the generation of transgenic mice achieving stable integration and some expression of foreign DNA. This technique attracted considerable attention in the following years when it became clear that the newly introduced genes were in­corporated into the germline of mice and that some of the foreign genes were found to be efficiently expressed.

The ability to introduce genes into the germline of mice (and other mammals) and the successful expression of the inserted gene within an organism provides new insights and opportunities for biomedical re­search. Transgenic technologies constitute an increasingly improtant tool to study the regulation and function of genes within the intact or­ganism. They can be applied to a variety of different fields to analyze, for example, disease processes initiated and/or caused by the ex­pression of certain gene products, to examine aspects of tumor devel­opment and techniques can be used to introduce human genes into the mouse/rat/rabbit background to study their function and to provide al­ternatives for the large-scale production of important but rare proteins, such as hormones in the milk of transgenic animals.

The different experimental strategies employing either gain-of­function or loss-of-function approaches in particular through the use of homologous recombination in embryonic stem cells allow the gener­ation of specific animal models for human diseases. The detailed ana­lysis of the underlying molecular mechanisms will provide now in­sights into the genetic origin of certain diseases and will lead to a

VI Preface

Abb. I. The participants of the workshop

better understanding of normal and abnormal physiological processes. This knowledge will improve also our diagnostic tools and will en­hance the development of novel therapeutic interventions. We hope that this book will illustrate some of the current concepts used in trans­genic research, emphasizing the application in the field of animal models for human diseases, and that it will serve as a basis to stimulate discussions for current and future basic and applied research.

Erwin F. Wagner Franz Theuring

Contents

The Human Renin-Angiotensin System in Transgenic Rats -New Tools for Antihypertensive Therapy Jurgen Wagner, Martin Paul, and Detlev Ganten ......... .

2 Probing the Genetics of Atherosclerosis in Transgenic Mice Edward Rubin and Joshua Schultz. . . . . . . . . . . . . . . . . . . . .. 25

3 The PrP-Iess Mouse: A Tool for Prion Research Charles Weissmann, Hansruedi Bueler, Marek Fischer, and Michel Aguet ................................... 39

4 The Carboxy terminal Fragment of the Alzheimer Amyloid Protein Precursor Causes Neurodegeneration In Vivo Rachael L. Neve, Michael R. Kozlowski, Anja Kammerscheidt, and Christine F. Hohmann. . . . . . . . .. 57

5 Transgenic Models of Chronic Arthritis and of Systemic Tumour Necrosis Factor-Mediated Disease in Mice Expressing Human Tumour Necrosis Factor George A. Kollias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 73

6 Mammary Neoplasia in Mouse Mammary Tumor Virus-Transforming Growth Factor ex Transgenic Mice Robert J. Coffey and Peter J. Dempsey. . . . . . . . . . . . . . . . .. 91

VIII

7 Exploring the Pathogenic Potential of c-fos, Polyoma Middle T and Human Foamy Virus in Transgenic Mice

Contents

Envin F. Wagner and Adriano Aguzzi . . . . . . . . . . . . . . . . .. lO9

8 Transgenic Animals as Bioreactors for Therapeutic and Nutritional Proteins Lothar Hennighausen, Avi Shamay, Priscilla A. Furth, Robert A. McKnight, Caird Rexroad Jr., Vern G. Pursel, and Robert J. Wall. . . . . . . . .. . . .. . . . . . . . . . . .. .. . . ... 129

9 Targeted Inactivation of the Muscle Regulatory Genes Myf-5 and MyoD: Effect on Muscle and Skeletal Development Michael A. Rudnicki, Thomas Braun, Hans-Henning Arnold, and Rudolf Jaenisch . . . . . . . . . . . .. 143

List of Contributors

Aguet, Michel Institut fUr Molekularbiologie I, Universitat Zurich, CH-8093 Zurich, Switzerland

Aguzzi, Adriano Research Institute of Molecular Pathology (IMP), Dr. Bohr-Gasse 7, A-I030 Vienna, Austria

Arnold, Hans-Henning Department of Toxicology, University of Hamburg Medical School, Grindelallee 117, W-2000 Hamburg 13, Germany

Bueler, Hansruedi Institut fur Molekularbiologie I, Universitat Zurich, CH-8093 ZUrich, Switzerland

Braun, Thomas Department of Toxicology, University of Hamburg Medical School, Grindelallee 117, W-2000 Hamburg 13, Germany

Coffey, Robert 1. Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA

x List of Contributors

Dempsey, Peter 10 Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA

Fischer, Marek Institut fi.ir Molekularbiologie I, Universitat Zi.irich, CH-8093 Zi.irich, Switzerland

Furth, Priscilla A. Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA

Ganten, Detlev Max Delbri.ick Center for Molecular Medicine, W -1000 Berlin -B uch, Germany

Hennighausen, Lothar Laboratory of Biochemistry and Metabolism, National Institutes of Health, Bethesda, MD 20892, USA

Hohmann, Christine Fo Molecular Neurogenetics Laboratory, 202 MRC, McLean Hospital, 115 Mill Street, Belmont, MA 02178, USA

laenisch, Rudolf Whitehead Institute for Biomedical Research and Department of Biol­ogy, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142, USA

Kammerscheidt, Anja Molecular Neurogenetics Laboratory, 202 MRC, McLean Hospital, 115 Mill Street, Belmont, MA 02178, USA

Kollias, George A. Laboratory of Molecular Genetics, Hellenic Pasteur Institute, 127 Vas Sofias Avo, Athens 115221, Greece

List of Contributors XI

Kozlowski, Michael R. Molecular Neurogenetics Laboratory, 202 MRC, McLean Hospital, 115 Mill Street, Belmont, MA 02178, USA

McKnight, Robert A. Laboratory of Biochemistry and Metabolism, National Institutes of Health, Bethesda, MD 20892, USA

Neve, Rachael L. Molecular Neurogenetics Laboratory, 202 MRC, McLean Hospital, 115 Mill Street, Belmont, MA 02178, USA

Paul, Martin German Institute for High Blood Pressure Research, Department Phar­macology, University of Heidelberg, 1m Neuenheimer Feld 366, W -6900 Heidelberg, Germany

Pursel, Vern G. Mapping Laboratory, United States Department of Agriculture, Belts­ville, MD 20705, USA

Rexroad, Caird Jr. Mapping Laboratory, United States Department of Agriculture, Belts­ville, MD 20705, USA

Rubin, Edward Life Sciences Division, 1 Cyclotron Road, Lawrence Berkeley Labora­tory, Berkeley, CA 94720, USA

Rudnicki, Michael A. Whitehead Institute for Biomedical Research and Department of Biol­ogy, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142, USA

Schultz, Joshua Life Sciences Division, 1 Cyclotron Road, Lawrence Berkeley Labora­tory, Berkeley, CA 94720, USA

XII List of Contributors

Shamay, Avi Laboratory of Biochemistry and Metabolism, National Institutes of Health, Bethesda, MD 20892, USA

Wagner, Erwin F. Research Institute of Molecular Pathology (IMP), Dr. Bohr-Gasse 7, A-I030 Vienna, Austria

Wagner, liirgen German Institute for High Blood Pressure Research, Department Phar­macology, University of Heidelberg, 1m Neuenheimer Feld 366, W -6900 Heidelberg, Germany

Wall, Robert 1. Mapping Laboratory, United States Department of Agriculture, Belts­ville, MD 20705, USA

Weissmann, Charles Institut fUr Molekularbiologie I, Universitat Zurich, CH-8093 Zurich, Switzerland