Transgenic Mice in Biomedical Research

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Transgenic Mice in Biomedical Research

Transgenic Mice in Biomedical Research

J. Willem Voncken and Marten Hofker
University of Maastricht, Maastricht, The Netherlands

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Genetically modified mouse models have become a crucial tool in present day biomedical research. Modifying genes in mice provides an excellent approach to unravel gene function at the molecular and cellular level, as well as its role in the
physiology and pathology of the intact organism. By doing so, numerous models have been developed that reliably replicate diseases in humans, thereby providing insight in disease mechanisms and paving the way toward prevention and therapy. Crucial for these advances has been the ability to modulate gene expression at will. It is possible to increase or decrease gene expression, or eliminate the expression of a
gene completely. These alterations can be made cell typespecific and even inducible or reversible.Moreover, it is possible to replace mouse genes with the cognate human
gene carrying a specificmutation. This chapterwill dealwith the essential approaches in transgenic mouse research and its impact on biomedical research.

1 A Brief History of Mice 508
1.1 Mouse Genetics 508
1.2 Molecular Mouse Genetics 510
1.2.1 Brief Overview of Developments in Transgenesis 511
1.2.2 Brief Overview of Developments in Gene Targeting 512

2 Transgenesis; Basics and Technology 513
2.1 Transgene Design 513
2.1.1 Origin and Structure of the Transgene 513
2.1.2 Regulatory Elements 515
2.2 Pronuclear Injection 518
2.3 Biotechnological Procedures 518

3 Gene Targeting; Basics and Technology 521
3.1 Targeting Vector Design 521
3.2 Embryonic Stem (ES) Cells 524
3.3 Genesis of Mosaic Embryos 524
3.4 Biotechnological Procedures 526

4 Refinements to the Models 527
4.1 Fully ES Cellderived Embryos 527
4.2 Conditional Transgenesis 529
4.3 Conditional Gene Targeting 530
4.3.1 Controlled CRE Expression 532
4.4 Knockins: Humanized Mice 533

5 Random Mutagenesis in ES Cells 536
5.1 Gene Trap Mutagenesis 537
5.2 Retroviruses and Transposable Elements in Random
Mutagenesis 538
5.3 Random Enu Mutation 539

6 Phenotype Analysis 539

7 Perspectives 540
7.1 Partial Transgenesis; Viral Shuttles 540
7.2 RNA Interference; Posttranscriptional Gene Silencing

Encyclopedia of Molecular Cell Biology and Molecular Medicine, 2nd Edition. Volume 14
Edited by Robert A. Meyers.
Copyright  2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim