Front cover 1
Preface 8
Editors 10
Contributors 12
Table of Contents 16
1 20
Genetically Engineered Mice: Past, Present, and Future 20
Generation of Mutant Mice 20
Gene Mapping 22
Maintenance and Archiving 22
Phenotyping Approaches 23
Summary 24
References 24
2 30
Sharing Research Tools: The Laboratory Mouse 30
1980 31
Cold Spring Harbor 32
The \u201cHarvard Mouse\u201d 33
Cre-Lox 33
NIH and the Memoranda of Understanding (MOU) 34
NIH Policy 35
Issues Raised in NIH Sharing Policy 37
Definition of Research Tools 37
Reach-Through Rights 37
Patenting Mice 39
Sharing Mice within Academia 39
Jackson Mouse Repository 40
The Research Exemption 41
References 43
3 46
Managing Success: Mutant Mouse Repositories 46
TABLE OF CONTENTS 46
Introduction 46
Setting the Stage 47
The Researcher/Repository Interface 48
Submission Policies 49
Donor Benefits 49
Costs Associated with Donation 50
Finding and Obtaining Mice 50
Repositories 51
The Jackson Laboratory 51
Mouse Mutant Resource (MMR) 51
The Induced Mutant Resource (IMR) 52
Type 1 Diabetes Resource (T1DR) 52
Mouse Mutant Regional Resource Centers (MMRRC) 52
Mouse Models of Human Cancers Consortium (MMHCC) Mouse Repository 53
RIKEN Bioresource Center (BRC) 53
Center for Animal Resources and Development (CARD) 54
European Mouse Mutant Archive (EMMA) 54
References 54
4 58
Mouse Genome Informatics: Database Access to Integrated Phenotype Data 58
History of MGI 58
Integrated Data within MGI 61
Phenotype Information within MGI on Genetically Engineered and Mutant Mice 62
Gene Expression Data 62
The Gene Expression Data Query Form 63
Mouse Tumor Biology Data 63
Alleles and Phenotype Data 66
Summary 71
References 72
5 76
Genetic Resource Databases in Japan 76
Establishment of the Resource Information Archive in Japan 76
Mouse and Rat Resource Databases in Japan 77
CARD R-DB 77
Riken GSC/BRC DB 77
NIG Mouse DB 78
Mouse Polymorphism DB 78
Rat DB 78
Future Directions 78
6 80
Computational Pathology: Challenges in the Informatics of Phenotype Description in Mutant Mice 80
Introduction: Representing Mutant Mouse Phenotypes 80
Pathbase and the Development of a Mouse Pathology Ontology 83
The Mouse Pathology (MPATH) Ontology 85
Other Approaches to a Pathology Description Framework 88
The Development of MPATH: Problems and Pitfalls in the Classification of Lesions 90
Diseases and the Pathologic Responses 91
Discussion 92
Morphological and Molecular Descriptions for Pathology 92
Handling Mutant Phenotypes 94
Acknowledgments 96
References 96
7 102
Biological Methods for Archiving and Maintaining Mutant Laboratory Mice 102
Introduction 103
Cryopreserving the Mouse 104
Dissemination of Mouse Models as Frozen Materials 105
Embryo Cryopreservation: An Overview 105
Controlled Rate Freezing 106
Methods for Controlled Rate Freezing 106
Equipment and Reagents 106
Solutions 107
Freezing Procedure 107
Thawing 108
Additional Considerations When Freezing Embryos and Gametes 109
Freeze-Drying: An Overview 109
Freeze-Drying Method 109
Equipment and Reagents 110
Solution 110
Preparation of Epididymal Spermatozoa 110
Freeze-Drying of Spermatozoa 110
Rehydration of Freeze-Dried Spermatozoa and ICSI 110
Anticipated Results 111
Vitrification: An Overview 111
Methods for Vitrification of Mouse Embryos 111
Equipment and Reagents 111
Solutions 112
Embryo Cooling 112
Thawing 113
Cryopreservation of Mouse Spermatozoa 114
Freezing Procedure 116
Equipment and Reagents 116
Solutions 116
Cryopreservation Method 117
Thawing 117
Method Used for In Vitro Fertilisation 117
Equipment and Reagents 118
Solutions 118
IVF Setup Procedure 118
Sperm Sample Preparation-Freshly Harvested Sperm 118
Sperm Sample Preparation-Cryopreserved Sperm 119
Harvesting Oocytes 120
Washing and Culturing the Fertilised Oocytes 120
Cryopreservation of Mouse Oocytes 120
Methods for Oocyte Freezing 121
Equipment and Reagents 121
Solutions 121
Freezing Procedure 121
Thawing 122
Cryopreservation of Mouse Ovarian Tissue 123
Methods for Ovary Freezing 123
Equipment and Reagents 123
Solutions 123
Freezing Procedure 124
Thawing 124
How Do You Define an Adequately Archived Stock? 125
Long-Term Survival of Cryopreserved Germplasm 125
Mouse Mutant Resources 126
Concluding Remarks 126
References 127
Appendix 129
8 132
Mouse Genetic Resources without Germ Cells: Somatic Cell Nuclear Transfer and ES Technology 132
Introduction 132
History of Somatic Cell Cloning and Application 133
Technical Determinants in Cloning 134
The Abnormality of Cloned Mice 135
Generation of ntES Cell Lines from Adult Somatic Cells 137
Conclusion 140
Acknowledgment 140
References 141
9 144
The Present Status of Somatic Cell Cloning 144
Introduction 144
Why Do Abnormalities Occur? 145
Abnormalities Associated with Somatic Cell Nuclear Transfer Cloning 145
Stages When Abnormalities Develop 145
Clone-Specific Abnormalities 146
Typical or Varied Abnormalities 146
Effects of Donor Cells 147
Future Directions 148
Conclusions 148
References 148
10 150
Exchangeable Gene Trapping 150
Gene Trapping-Principle, Advantages, and Disadvantages 150
Cre-Mutant Lox Site-Specific Integration System 153
pU-17 Exchangeable Trap Vector 158
References 159
11 162
Genetic Monitoring of Mice 162
Introduction: Genetic Contaminations Reported in the Past 162
Spontaneous Mutant and Genetically Engineered Mouse Phenotypes Vary with Genetic Background 163
Genetic Monitoring (Genetic Quality Testing) of Live Mice 165
Markers for Genetic Monitoring 165
Sets of Markers for Genetic Quality Testing 166
Categories of Genetic Quality Testing 168
Schedule of Genetic Monitoring 168
Test Frequency 168
Monitoring Schedule 169
Genetic Monitoring for Cell Lines, Gametes, and Embryos 169
Species Identification 171
Sex Identification 171
Strain Identification 171
Genotyping of Transgenes and Targeted Genes 172
Development of a Genetic Monitoring Kit 174
Conclusion 174
References 175
12 176
Microbiological Monitoring of Laboratory Mice 176
Introduction 176
Microbial Exclusion Planning 177
Elements of Routine Microbiologic Monitoring 179
Summary 182
References 182
13 184
Effect of Intestinal Flora on Phenotype 184
Effect of Intestinal Flora on Tumorigenesis in GEM Mice 185
Colon Tumors in Gnotobiotic RasH2 Transgenic Mice 185
Standardization of Intestinal Flora 187
References 189
14 192
Helicobacter pylori and Stomach Cancer 192
Relation between H. pylori Infection and Stomach Cancer in Mongolian Gerbils Treated with Chemical Carcinogens 192
Phenotypic Classification of Intestinal Metaplasia and Regulation of Gastric and Intestinal Epithelial Phenotypic Expression by Specific Transcription Factors 193
Reversibility of Tumorlike Lesions Induced by Hp in Mongolian Gerbils 194
Is IM a Premalignant Lesion in Gastric Cancer? 195
Gastric and Intestinal Phenotypic Expression of Gastric Cancer Cells 196
Stem Cells of Gastric and Intestinal Mucosa and Clonal Growth of Gastric Cancer 197
Conclusion 197
References 198
15 204
Professional Use of Mutant Laboratory Mice in Research 204
Uses of Laboratory Mice in Skin and Hair Research 205
Characterizing Mutant Mice 205
Spontaneous Mutants 207
Genetically Engineered Mice 208
Identifying Mutant Mice Resulting from Mutations in Genes of Interest 208
Correlation with the Human Disease 209
Xenographs 209
Allografts 210
Exogenous Compounds 210
Internet Resources for Genetic and Phenotypic Information about Mice 211
Mouse Genome Informatics Web Site 211
Searching MGI by Gene Name or Symbol 212
Searching MGI by Phenotype Keywords 215
Searching MGI by Sequence Similarity 217
MGI User Support 218
Obtaining Mice for Use in Research 218
Nonprofit Institutions 219
Commercial Vendors 221
Other Web-Based Resources Relevant to Skin and Hair Research 222
Acknowledgments 223
References 223
16 230
Phenotyping Postpartum Mutant Laboratory Mice and Determining Their Value for Human Diseases 230
Introduction 230
Background Information and Resources 231
Research Approaches to Mutant Mouse Characterization 231
Differentiating Mutant Phenotypes from Infectious Diseases 233
Colony Establishment 233
Determining the Genetic Nature of the Mutant Phenotype 234
Phenotypic Characterization, General Issues 234
Which Mice and How Many to Analyze? 235
Comparison with Human and Domestic Animal Diseases 236
Summary 237
References 238
17 242
Common Diseases Found in Inbred Strains of Laboratory Mice 242
References 244
18 252
Colon Cancer and Polyposis Models 252
Introduction 252
Mouse Models for Familial Adenomatous Polyposis (FAP) 253
ApcMin Mice, ApcD716 Mice, Apc1638N Mice, and Other Apc Mutant Mice 253
Modifier Genes of Apc Intestinal Polyposis 255
Mutations in DNA Mismatch Repair Genes 256
Stabilizing b-Catenin Mutant Mice 257
Mouse Models for Gastrointestinal Hamartoma Syndromes 257
Mouse Models for Colon Cancer 259
Mouse Models for Hereditary Nonpolyposis Colon Cancer 259
Additional Mutations in ApcMin Mice, ApcD716 Mice, or Apc1638N Mice 260
Colon Cancer Models with Mutations in Other Genes 260
Mouse Models for Colon Cancer Associated with Inflammatory Bowel Disease 262
Mouse Models for Tumor Chemotherapy and Chemoprevention 262
Acknowledgment 264
References 264
Note Added in proof 270
19 272
Phenotypic Analysis of Mice with Steroid Deficiency 272
Introduction 272
Results 274
Cyp11a1 Null Mice Rescued with Corticosteroids Exhibit Growth Retardation 274
Sex Reversal and Cryptorchidism of Cyp11a1 Null Male Mice 275
Internal Reproductive Tract Phenotype of Cyp11a1 Null Mice 276
Defect of Male Accessory Sex Organ Differentiation in Cyp11a1 Null Mice 276
Genital Tract Infantilism of Cyp11a1 Null Female Mice 277
Histological Modifications in Genital Tract of Cyp11a1 Null Mice 278
Discussion 279
Acknowledgments 280
References 280
20 282
External Genitalia Development: A Model System to Study Organogenesis 282
External Genitalia Development: A Model for Organogenesis? 284
Emergence of Growth Factors: Fibroblast Growth Factors (FGFs) as a Beginning of Growth Factor Analysis of External Genitalia Formation 288
Implications for Understanding Human Birth Defects Based on Molecular Embryology for External Genitalia Development 289
Role of Fgf10 During External Genitalia Formation: The First Case of Gene Knock-Out Mouse Model for External Genitalia Development 289
Identification of an Essential Epithelial Gene: The Role of Shh in Urethral Plate Epithelia v.s. Mesenchymal Fgf10 290
Genes Necessary for Setting Initial Developmental Field: Genetic Cascades Necessary for External Genitalia Outgrowth Induction 290
The Role of Developing Epithelia in Epithelial-Mesenchymal Interaction: The Development of External Genitalia and Embryonic Gut 291
Role of Bone Morphogenetic Protein (Bmp) Genes in External Genitalia Development 292
Do Signaling Epithelia Explain All Aspects Of External Genitalia Development? The Role of DUE 293
Acknowledgment 293
References 294
21 298
Genetic Approaches to Investigate Retinoic Acid Functions in Mouse Development 298
Introduction 298
RA Receptors Have Pleiotropic and Mostly Redundant Developmental Functions 300
Retinoic Acid Synthesis Is Enzymatically Regulated in Embryonic Tissues 301
Differential Expression Patterns of Murine Retinaldehyde Dehydrogenases 302
RALDH2 Is Mainly Responsible for RA Synthesis at Early Embryonic Stages 304
RA-Rescue of Null Mutant Embryos Unveils Additional RALDH2 Developmental Functions 305
Decreased RALDH2-Mediated RA Synthesis Leads to a DiGeorge Syndromelike Phenotype 307
Conditional Mutagenesis: An Alternative Approach to Investigate Tissue-Specific RALDH2 Functions 308
Acknowledgments 310
References 310
22 314
Mouse Models For Developmental Biology: Functional Analysis of Ror and Wnt Signaling 314
Introduction 314
Phenotypes of the Ror1 and Ror2 Mutant Mice 316
The Ror2 Mutant Mice as a Model for Human Genetic Disorders 317
Comparison of Phenotypes of Ror2 and Wnt5a Mutant Mice 317
Physical and Functional Interactions Between Ror2 and Wnt5a 318
Tyrosine Kinase-Dependent and -Independent Functions of Ror2 319
Acknowledgments 319
References 320
Index 322
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e 324
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x 333