Handbook of In Vivo Chemistry in Mice: From Lab to Living System 978-3527344321, 3527344322

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Handbook of In Vivo Chemistry in Mice

Handbook of In Vivo Chemistry in Mice From Lab to Living System

Edited by Katsunori Tanaka Kenward Vong

Editors Prof. Katsunori Tanaka

RIKEN Biofunctional Synthetic Chemistry Lab 2-1 Hirosawa, Wako 351-0198 Saitama Japan

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

Dr. Kenward Vong

RIKEN Biofunctional Synthetic Chemistry Lab 2-1 Hirosawa, Wako 351-0198 Saitama Japan Cover

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The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at . © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Print ISBN: 978-3-527-34432-1 ePDF ISBN: 978-3-527-34437-6 ePub ISBN: 978-3-527-34441-3 oBook ISBN: 978-3-527-34440-6 Typesetting SPi Global, Chennai, India Printing and Binding

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Contents

1

Summary of Currently Available Mouse Models 1 Ami Ito, Namiko Ito, Kimie Niimi, Takashi Arai, and Eiki Takahashi

1.1 1.2 1.3 1.3.1 1.3.2 1.3.3 1.3.4 1.3.5 1.3.6 1.4 1.4.1 1.4.2 1.4.3 1.4.4 1.4.5 1.4.6 1.5 1.6 1.7 1.8 1.9 1.10 1.11 1.11.1 1.11.2 1.12 1.13 1.14 1.15 1.16 1.17 1.18

Introduction 1 Origin and History of Laboratory Mice 2 Laboratory Mouse Strains 3 Wild-Derived Mice 3 Inbred Mice 4 Hybrid Mice 4 Outbred Stocks 8 Closed Colony 8 Congenic Mice 8 Mutant Mice 9 Spontaneous 9 Transgenesis 9 Targeted Mutagenesis 11 Inducible Mutagenesis 13 Cre–loxP System 13 CRISPR/Cas9 System 15 Resources of Laboratory Strains 16 Germ-Free Mice 16 Gnotobiotic Mice 18 Specific Pathogen-Free Mice 18 Immunocompetent and Immunodeficient Mice 18 Mouse Health Monitoring 19 Production and Maintenance of Mouse Colony 19 Production Planning 19 Breeding Systems and Mating Schemes 19 Mating 21 Gestation Period 21 Parturition 21 Parental Behavior and Rearing Pups 21 Growth of Pups 22 Reproductive Lifespan 23 Record Keeping and Colony Organization 23

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Contents

1.19 1.20

Animal Identification 24 Animal Models in Preclinical Research References 29

2

General Notes of Chemical Administration to Live Animals 33 Ami Ito, Namiko Ito, Takashi Arai, Eiki Takahashi, and Kimie Niimi

2.1 2.2 2.2.1 2.2.2 2.3 2.3.1 2.3.2 2.3.3 2.3.4 2.4 2.4.1 2.4.2 2.5 2.6 2.6.1 2.6.1.1 2.6.1.2 2.6.2 2.6.2.1 2.6.2.2 2.6.2.3 2.6.2.4 2.6.2.5 2.6.2.6 2.6.2.7 2.6.2.8 2.6.2.9 2.6.2.10

Introduction 33 Restraint 34 One-Handed Restraint 34 Two-Handed Restraint 34 Substances 34 Substance Characteristics 34 Vehicle Characteristics 35 Frequency and Volume of Administration 36 Needle Size 37 Anesthesia 37 Inhaled Agents 38 Injectable Agents 38 Euthanasia 40 Administration 41 Enteral Administration 42 Oral Administration 42 Intragastric Administration 42 Parenteral Administration 42 Subcutaneous Administration 44 Intraperitoneal Administration 44 Intravenous Administration 46 Intramuscular Administration 46 Intranasal Administration 46 Intradermal Administration 46 Epicutaneous Administration 46 Intratracheal Administration 51 Inhalational Administration 51 Retro-orbital Administration 52 References 53

3

Optical-Based Detection in Live Animals 55 Mikako Ogawa and Hideo Takakura

3.1 3.1.1 3.1.2 3.1.3 3.2 3.2.1 3.2.2 3.2.3 3.2.4

Introduction 55 Basics of Luminescence 55 Appropriate Wavelengths for Live Animal Imaging 56 Advantages and Disadvantages of In Vivo Optical Imaging 58 Fluorescence Imaging in Live Animals 58 Fluorescent Molecules for Live Animal Imaging 58 How to Detect Fluorescence in Live Animals? 61 Activatable Probes 62 Microscope 68

24

Contents

3.2.5 3.3 3.3.1 3.3.1.1 3.3.1.2 3.3.1.3 3.3.2 3.3.3 3.4

Application of Fluorescence Imaging to Drug Development 68 Luminescence Imaging in Live Animals 69 Luminescence Systems for Live Animal Imaging 70 Firefly/Beetle Luciferin–Luciferase System 70 Coelenterazine-Dependent Luciferase System 76 Chemiluminescence System 82 How to Detect Luminescence in Live Animals? 84 Luciferase-Based Bioluminescence Probes for In Vivo Imaging 84 Summary 87 References 87

4

Ultrasound Imaging in Live Animals 103 Francesco Faita

4.1 4.2 4.3 4.4 4.5 4.5.1 4.5.2 4.5.3

Introduction 103 High-Frequency Ultrasound Imaging 105 Ultrasound Contrast Agents 109 Photoacoustic Imaging 112 Preclinical Applications 115 Cardiovascular 115 Oncology 120 Developmental Biology 121 References 123

5

Positron Emission Tomography (PET) Imaging in Live Animals 127 Xiaowei Ma and Zhen Cheng

5.1 5.2 5.3 5.4 5.5 5.5.1 5.5.2 5.5.3 5.5.4 5.5.5 5.5.6 5.5.7 5.5.8 5.6 5.6.1 5.6.1.1 5.6.1.2 5.6.1.3 5.6.1.4 5.6.1.5 5.6.2

Introduction 127 Brief History of PET 128 Principles of PET 129 Small-Animal PET Scanners 133 PET Imaging Tracers 134 Metabolic Probe 134 Specific Receptor Targeting Probe 135 Gene Expression 136 Specific Enzyme Substrate 137 Microenvironment Probe 137 Biological Processes 138 Perfusion Probes 140 Nanoparticles 140 PET in Animal Imaging 141 PET in Oncology Model 141 Cancer Diagnosis 142 Personal Treatment Screening 142 Therapeutic Effect Monitoring 143 Radiotherapy Planning 144 Drug Discovery 144 PET in Cardiology Model 145

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5.6.3 5.6.4 5.7 5.8

PET in Neurology Model 146 PET Imaging in Other Disease Models 147 PET Image Analysis 147 Outlook for the Future 148 Reference 149

6

Single-Photon Emission Computed Tomographic Imaging in Live Animals 151 Yusuke Yagi, Hidekazu Kawashima, Kenji Arimitsu, Koki Hasegawa, and Hiroyuki Kimura

6.1 6.2 6.2.1

Introduction 151 SPECT Devices Used in Small Animals 152 Innovative Preclinical Full-Body SPECT Imager for Rats and Mice: γ-CUBE 155 Innovative Preclinical Full-Body PET Imager for Rats and Mice: β-CUBE 156 Innovative Preclinical Full-Body CT Imager for Rats and Mice: X-CUBE 156 Animal Monitoring: Its Importance and Overview of MOLECUBES’s Integrated Solution to Advance Physiological Monitoring 157 Selected Applications Acquired on the CUBES 157 SPECT Imaging with γ-CUBE 158 PET Imaging with β-CUBE 158 CT Imaging with X-CUBE 161 Characteristics of SPECT Radionuclides and SPECT Imaging Probes 162 Characteristics of SPECT Radionuclides 162 Characteristics of SPECT Imaging Probes 162 Radiolabeling 163 Characteristic of Radiolabeling 164 Radiolabeling with Technetium-99m 164 Radiolabeling with Iodine-123 and Iodine-131 171 Radioactive Iodine Labeling for Small Molecular Compounds 171 Aromatic Electrophilic Substitution Reaction 171 In Vivo Imaging of Disease Models 172 Imaging of Central Nervous System Disease 173 Alzheimer’s Disease 173 Parkinson’s Disease 174 Cerebral Ischemia 176 Imaging of Cardiovascular Disease 177 Atherosclerotic Plaque 177 Myocardial Ischemia 177 Imaging of Cancer 178 Conclusions 179 References 180

6.2.2 6.2.3 6.2.4 6.2.5 6.2.5.1 6.2.5.2 6.2.5.3 6.3 6.3.1 6.3.2 6.4 6.4.1 6.4.2 6.4.3 6.4.4 6.4.5 6.5 6.5.1 6.5.1.1 6.5.1.2 6.5.1.3 6.5.2 6.5.2.1 6.5.2.2 6.5.2.3 6.6

Contents

7

Radiotherapeutic Applications 185 Koki Hasegawa, Hidekazu Kawashima, Yusuke Yagi, and Hiroyuki Kimura

7.1 7.2 7.2.1 7.2.2 7.3 7.3.1 7.3.2 7.3.3 7.3.4 7.3.4.1 7.3.4.2 7.3.4.3 7.3.4.4 7.3.4.5 7.3.5 7.3.5.1 7.3.5.2 7.3.5.3 7.3.6 7.4 7.4.1 7.4.2 7.4.3 7.4.4 7.4.5 7.4.5.1 7.4.5.2 7.5

Introduction 185 Radionuclide Therapy in Tumor-Bearing Mice 186 Radiotherapy with β-Emitting Nuclides 186 Radiotherapy Using α-Emitting Nuclides 188 Radiolabeling Strategy 191 Labeled Target Compounds 191 211 At-Labeled Compounds 192 Chelating Agents for 90 Y, 177 Lu, 225 Ac, 213 Bi 193 Peptides for Radionuclide Therapy 195 Octreotate (TATE) and [Tyr3 ]-Octreotide (TOC) 195 NeoBOMB1 196 Pentixather 196 PSMA-617 196 Minigastrin 196 Antibodies for Radionuclide Therapy 197 Lintuzumab 197 Rituximab 197 Trastuzumab 197 Examples of Radiotherapeutic Agents and Target Diseases 197 Radiotheranostics 200 Radiotheranostics Probe 200 Our Approach to Radiotheranostic Probe Development 202 Expectations and Challenges in Radiotheranostics 202 Boron Neutron Capture Therapy (BNCT) 203 Current Status of BNCT Drugs 204 4-Borono-l-Phenylalanine (BPA) 204 Sodium Borocaptate (BSH) 204 Conclusion 205 References 205

8

Metabolic Glycan Engineering in Live Animals: Using Bio-orthogonal Chemistry to Alter Cell Surface Glycans Danielle H. Dube and Daniel A. Williams

8.1 8.2 8.2.1 8.2.2 8.3 8.3.1 8.3.2 8.4

209

Introduction 209 Overview of Metabolic Glycan Engineering 210 Origin of Metabolic Glycan Engineering 210 Expansion of the Methodology to Include Unnatural Functional Groups and Bio-orthogonal Elaboration 213 Bio-orthogonal Chemistries that Alter Cell Surface Glycans 216 Bio-orthogonal Chemistries Amenable to Deployment in Live Animals 216 Bio-orthogonal Chemistries Amenable to Deployment on Cells 221 Permissive Carbohydrate Biosynthetic Pathways 223

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8.4.1 8.4.2 8.5 8.5.1 8.5.2 8.5.3 8.5.4 8.5.5 8.5.6 8.6 8.6.1 8.6.2 8.7 8.7.1 8.7.2 8.7.3 8.8 8.8.1 8.8.2 8.8.3

Deployment of Unnatural Monosaccharides in Mammalian Cells 223 Unnatural Sugars that Label Glycans on Bacterial Cells 225 Cell- and Tissue-Specific Delivery of Unnatural Sugars 226 Harness Inherent Differences in Carbohydrate Biosynthesis 227 Metabolically Label Cells Ex vivo Before Introducing Them In vivo 227 Label Tissues or Organs In vivo Before Analyzing them Ex vivo 229 Employ Tissue-Specific Enzymes to Release Monosaccharide Substrates 229 Deliver Monosaccharide Substrates via Liposomes 231 Use Tissue-Specific Transporters to Induce Monosaccharide Uptake 234 Applications of Metabolic Glycan Labeling in Mice 234 Imaging Glycans in Mice 234 Covalent Delivery of Therapeutics in Mice 236 Beyond Mice: Metabolic Glycan Engineering in Diverse Animals 237 Zebra Fish 237 Worms 239 Plants 240 Conclusions and Future Outlook 240 Metabolic Glycan Engineering Offers a Test Bed for Bio-orthogonal Chemistries 240 New Bio-orthogonal Reactions Could Transform the Field 241 Basic Questions About Glycans Within Living Systems Remain Unanswered 241 Acknowledgments 241 References 241

9

In Vivo Bioconjugation Using Bio-orthogonal Chemistry 249 Maksim Royzen, Nathan Yee, and Jose M. Mejia Oneto

9.1 9.1.1 9.1.2

Introduction 249 IEDDA Chemistry Between trans-Cyclooctene and Tetrazine 249 Synthesis of New Tetrazines and Characterization of Their Reactivity 251 Second Generation of IEDDA Reagents 251 Bond-cleaving Bio-orthogonal “Click-to-Release” Chemistry 251 In Vivo Applications of IEDDA Chemistry 251 Pretargeting Approach for Cell Imaging 252 Pretargeting Approach for In Vivo Imaging 256 Application of the Pretargeting Strategy for In Vivo Radio Imaging 259 In Vivo Drug Activation Using Bond-cleaving Bio-orthogonal Chemistry 260 Reloadable Materials Allow Local Prodrug Activation 265 Reloadable Materials Allow Local Prodrug Activation Using IEDDA Chemistry 266 Controlled Activation of siRNA Using IEDDA Chemistry 272

9.1.3 9.1.4 9.2 9.2.1 9.2.2 9.2.3 9.2.4 9.2.5 9.2.6 9.2.7

Contents

9.3

Future Outlook 274 References 277

10

In Vivo Targeting of Endogenous Proteins with Reactive Small Molecules 281 Naoya Shindo and Akio Ojida

10.1 10.2 10.2.1 10.2.2 10.2.3 10.3 10.3.1 10.3.2 10.3.3 10.3.4 10.3.5 10.4

Introduction 281 Ligand-Directed Chemical Ligation 282 Ligand-Directed Tosyl Chemistry 282 Ligand-Directed Acyl Imidazole Chemistry 284 Other Chemical Reactions for Endogenous Protein Labeling Labeling Chemistry of Targeted Covalent Inhibitors 287 Michael Acceptors 290 Haloacetamides 293 Activated Esters, Amides, Carbamates, and Ureas 295 Sulfur(VI) Fluorides 297 Other Warheads and Reactions 300 Conclusion 301 References 302

11

In Vivo Metal Catalysis in Living Biological Systems 309 Kenward Vong and Katsunori Tanaka

11.1 11.2 11.2.1 11.2.2 11.2.3 11.2.4 11.3 11.3.1 11.3.2 11.4

Introduction 309 Metal Complex Catalysts 310 Protein Decaging 310 Protein Bioconjugation 311 Small Molecule – Bond Formation 319 Small Molecule – Bond Cleavage 324 Artificial Metalloenzymes 332 ArMs Utilizing Naturally Occurring Metals 332 ArMs Utilizing Abiotic Transition Metals 335 Concluding Remarks 340 References 343

12

Chemical Catalyst-Mediated Selective Photo-oxygenation of Pathogenic Amyloids 355 Youhei Sohma and Motomu Kanai

12.1 12.2

Introduction 355 Catalytic Photo-oxygenation of Aβ Using a Flavin–Peptide Conjugate 357 On–Off Switchable Photo-oxygenation Catalysts that Sense Higher Order Amyloid Structures 358 Near-Infrared Photoactivatable Oxygenation Catalysts: Application to Amyloid Disease Model Mice 363 Closing Remarks 367 References 368

12.3 12.4 12.5

287

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13

Nanomedicine Therapies 373 Patrícia Figueiredo, Flavia Fontana, and Hélder A. Santos

13.1 13.2 13.2.1 13.2.2 13.2.3 13.2.4 13.3 13.3.1 13.3.2 13.3.3 13.3.4 13.4

Introduction 373 Engineering Nanoparticles for Therapeutic Applications 375 Physicochemical Properties of NPs 375 Surface Functionalization 379 Stimuli-Responsive Nanomaterials 381 Route of Administration 384 Nanomedicine Platforms 384 Lipidic Nanoplatforms 384 Polymer-Based Nanoplatforms 389 Inorganic Nanoplatforms 391 Biomimetic Cell-Derived Nanoplatforms 393 Conclusions 394 References 395

14

Photoactivatable Targeting Methods 401 Xiangzhao Ai, Ming Hu, and Bengang Xing

14.1 14.2 14.2.1 14.2.2 14.3 14.4 14.4.1 14.4.2 14.4.3 14.5

Introduction 401 UV Light-Responsive Theranostics 403 UV Light-Triggered Photocaged Strategy 403 UV Light-Mediated Photoisomerization Strategy 405 Visible Light-Responsive Theranostics 408 Near-Infrared (NIR) Light-Responsive Theranostics 410 NIR Light-Mediated Drug Delivery Approach 411 NIR Light-Mediated Photodynamic Therapy (PDT) Approach 415 NIR Light-Mediated Photothermal Therapy (PTT) Approach 419 Conclusion and Prospects 421 Acknowledgment 423 References 423

15

Photoactivatable Drug Release Methods from Liposomes 433 Hailey I. Kilian, Dyego Miranda, and Jonathan F. Lovell

15.1 15.1.1 15.2 15.2.1 15.2.2 15.2.3 15.2.4 15.2.5

Introduction 433 Light-Sensitive Liposomes 434 Mechanisms of Light-Triggered Release from Liposomes 435 Light-Induced Oxidation 435 Photocrosslinking 436 Photoisomerization 438 Photocleavage 440 Photothermal Release 442 References 444

16

Peptide Targeting Methods 451 Ruei-Min Lu, Chien-Hsun Wu, Ajay V. Patil, and Han-Chung Wu

16.1 16.2

Introduction 451 Identification of Targeting Peptides 452

Contents

16.2.1 16.2.2 16.2.3 16.3 16.3.1 16.3.1.1 16.3.1.2 16.3.2 16.3.2.1 16.3.2.2 16.4 16.4.1 16.4.1.1 16.4.1.2 16.4.1.3 16.4.2 16.4.3 16.5

Natural Ligands and Biomimetics 452 Phage Display Peptide Library Screening 454 Synthetic Peptide Library Screening 458 Therapeutic Applications of Targeting Peptides 460 Therapeutic Peptides 460 Naturally Occurring Peptides 464 Peptide Conjugates 464 Drug Delivery 465 Peptide–Drug Conjugates 465 Peptide-Targeted Nanoparticles 467 Molecular Imaging Mediated by Targeting Peptides 469 Optical Imaging 470 Targeting Peptides for Tumor Imaging 471 Integrin αv β3 – RGD Tripeptide Targeting Probes: 471 Near-Infrared Imaging 472 Positron Emission Tomography 472 Magnetic Resonance Imaging 473 Summary and Future Perspectives 474 References 475

17

Glycan-Mediated Targeting Methods 489 Kenward Vong, Katsunori Tanaka, and Koichi Fukase

17.1 17.2 17.2.1 17.2.2 17.3 17.3.1 17.3.2 17.3.3 17.3.4 17.4 17.5 17.5.1 17.5.2 17.5.3 17.6

Introduction 489 Liver and Liver-Based Disease Targeting 491 Parenchymal Cell Targeting 492 Nonparenchymal Cell Targeting 498 Immune System Targeting 501 Alveolar Macrophage Targeting 503 Peritoneal Macrophage Targeting 503 Dendritic Cell Targeting 504 Brain Macrophage Targeting 504 Bacterial Cell Targeting 505 Cancer Targeting 506 Natural Monosaccharide-Based Methods 506 Synthetic Sugars 508 Complex Glycan Scaffold 511 Concluding Remarks 514 References 514 Index 531

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1 Summary of Currently Available Mouse Models Ami Ito, Namiko Ito, Kimie Niimi, Takashi Arai, and Eiki Takahashi RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan

1.1 Introduction It is estimated that laboratory mice comprise more than 80% of the animals used in research. Researchers have nearly 100 years of experience working with mice in the field in settings such as commercial rodent production sites, laboratories, academic institutions, and pharmaceutical companies and have also performed resource studies. Mice require relatively little space and do not have complex dietary needs. They are easy to physically manipulate and relatively inexpensive compared to other laboratory animals. Although this is problematic with some species, mice can be inbred, which enables inclusion of littermates as controls and production of large number of animals. Production of inbred strains means that their backgrounds can be defined. Given ideal conditions, mice can produce at least four generations in a year, meaning that multiple generations can be produced rapidly and followed for experimental purposes. As small mammals, they have a limited lifespan, which facilitates aging and multigenerational studies. Mice were the first mammals after humans to have their genome sequenced [1]. As there is approximately 85% homology between the mouse and human genomes, any given gene is most likely present in both the mouse and human genomes and will generally have a similar function [1]. This allows mice to serve as models of many human conditions and, more importantly, allows us to study basic mammalian genetics and other conserved systems in mammalian cells. The study of mutant mice has evolved from the exploration of the collections of the spontaneous coat color mutants maintained by nineteenth century mouse fanciers to the advent of several methods of directed manipulation of the mouse genome. A further explanation for the dominance of the mouse in research is the robustness of their embryos. These may be cryopreserved and cultured from the one-cell stage to the post-implantation stage. Advances in molecular technologies have improved our ability to create mouse models of human

Handbook of In Vivo Chemistry in Mice: From Lab to Living System, First Edition. Edited by Katsunori Tanaka and Kenward Vong. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2020 by Wiley-VCH Verlag GmbH & Co. KGaA.

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1 Summary of Currently Available Mouse Models

musuculus

domesticus

? bactrianus domesticus

(molossinus) castaneus

domesticus

Figure 1.1 Mice used in the laboratory are derived from a variety of sources.

disease by means of transgenesis, targeted mutagenesis, and the CRISPR/Cas9 system. These mutations continue to provide valuable research tools for the study of the functions of genes within the entire organism. Today, there are repositories of genetically mutant mice located around the world that provide scientists with access to models of many diseases, contributing substantially to our understanding of both basic biological pathways and disease mechanisms. This chapter describes the history of laboratory mice; the types of mouse strains available; the handling of mouse colonies, mouse cell lines, and strains; and the use of mouse models in preclinical studies.

1.2 Origin and History of Laboratory Mice Mice currently used in the laboratory are domesticated animals. Laboratory mice are fatter, slower, less aggressive, and more amenable to handling than their wild-caught counterparts. Mice likely originated on the Indian subcontinent and spread throughout the world with agriculture and human movement [2] (Figure 1.1). Contemporary mice have genetic contributions from both Mus musculus ssp. musculus and Mus musculus ssp. domesticus, and evidence indicates that Mus musculus ssp. molossinus and Mus musculus ssp. castaneus made smaller contributions. Therefore, mice should not be referred to by their species name but rather as laboratory mice or by a specific strain or stock name. Additionally, some recently developed laboratory mouse strains are derived wholly from other Mus species or other subspecies, such as Mus spretus. The source of many of the mouse strains currently in use is the mouse colony established by Miss Abbie Lathrop (1868–1918) in her small white farmhouse in Granby, Massachusetts [3]. Dr. William E. Castle (1867–1962), a pioneer in mouse genetics, purchased some of Lathrop’s mice and trained Dr. Clarence. C. Little (1888–1971), the founder of the Jackson Laboratory. Dr. Little bred

1.3 Laboratory Mouse Strains

C57BL/6 from Lathrop’s mouse number 57. The resulting C57BL/6 became the most frequently used strain of laboratory mice.

1.3 Laboratory Mouse Strains 1.3.1

Wild-Derived Mice

Wild-derived mice are descendants of mice originally caught in the wild. The available wild-derived strains are M. musculus ssp. musculus, M. musculus ssp. domesticus, M. musculus ssp. molossinus, M. musculus ssp. castaneus, Mus caroli, Mus hortulames, Mus praetextus, Mus pahari, and Mus spretus (Table 1.1). Wild-derived mice are genetically distinct from common laboratory mice in a number of complex phenotypic characteristics and are valuable tools for genetic evolution and systematics research. They enable mapping of both the single-gene traits and quantitative trait loci (QTL) contributing to complex phenotypes. Table 1.1 Origin of wild-derived inbred strains.a) Species

Geographic origin

Strain

M. musculus ssp. musculus

Kunratice, Czech Republic Lhotka, Czech Republic

PWD/PhJ PWK/PhJ

M. musculus ssp. domesticus

California, USA Lewes, Delaware, USA

CALB/RkJ LEWES/EiJ

Ohio, USA

MOR/RkJ

Tirano, Italy

TIRANO/Ei

Monastir, Tunisia

WMP/PasDnJ

Centreville, Queen Anne City, Maryland, USA

WSB/EiJ

Zalende, Switzerland

ZALENDE/Ei

Japan Fukuoka, Kyushu, Japan

JF1/Ms MOLC/RkJ, MOLD/RkJ

Mishima, Shizuoka, Japan

MSM/Ms

M. musculus ssp. castaneus M. caroli

Thailand

CASA/RkJ, CAST/EiJ

Thailand

Mus caroli/EiJ

M. hortulanus

Pancevo, Serbia

PANCEVO/EiJ

M. pahari

Thailand

Mus pahari/EiJ

M. spretus

Puerto Real, Cadiz Province, Spain

SPRET/EiJ

M. musculus ssp. molossinus

MOLF/EiJ, MOLG/DnJ

M., Mus. a) https://www.jax.org/search?q. Source: Data from Jax Mice Database − Wild-derived Inbred Website.

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1 Summary of Currently Available Mouse Models

1.3.2

Inbred Mice

Strains can be termed inbred if they have been mated brother × sister for 20 or more consecutive generations, and individuals of the strain can be traced to a single ancestral pair at the twentieth or subsequent generation. At this point, the individuals’ genomes will, on average, have only 0.01 residual heterozygosity (excluding any genetic drift) and can, for most purposes, be regarded as genetically identical. Inbred mouse strains exhibit specific characteristics (Table 1.2) and provide a uniform genetic background for accurate phenotypic evaluation.

1.3.3

Hybrid Mice

Mice that are the progeny of two inbred strains, crossed in the same direction, are genetically identical and can be designated using uppercase abbreviations of the two parents (maternal strain listed first), followed by F1. Note that the reciprocal F1 hybrids are not genetically identical and their designations are, therefore, different. Examples D2B6F1: Mouse that is the offspring of a DBA/2N mother and a C57BL6/J father. A full F1 designation is (DBA/2N x C57BL/6J)F1. B6D2F1: Mouse that is the offspring of a C57BL6/J mother and a DBA/2N father. A full F1 designation is (C57BL/6J x DBA/2N)F1. For the sake of clarity, the full strain symbols of the above cases should be given in any publication when the hybrids or crosses are first referred to. If a hybrid were to be constructed using a substrain known to differ from the “standard” strain genetically and/or phenotypically, the substrain should be indicated in the hybrid symbol: e.g. C3H/HeSn = C3Sn. The approved abbreviations for common mouse strains are listed below: 129: 129 strains (may include subtype; e.g. 129S6 for strain 129S6/SvEvTac) A: A strains, except for Heston substrains A/He: A/He (Heston substrains) AK: AKR strains B6J: C57BL/6J substrains B6N: C57BL/6N substrains C: BALB/c strains cBy: BALB/cBy (Bailey substrains) cWt: BALB/cWt (Whitten substrains) C3: C3H strains CBA: CBA strains, except Carter substrains CBA/Ca: CBA Carter substrains D1: DBA/1 strains D2: DBA/2 strains.

Table 1.2 Inbred strain of mice. Strain

Comment

Substrains

Comment

129

129 Strain has a high incidence of spontaneous testicular teratomas, although the incidence differs between substrains. They are widely used in the production of targeted mutations because of the availability of multiple embryonic stem (ES) cell lines derived from them. Major genetic variation exists between various sublines of the 129 “family.”

129S1/SvIm

A

This strain is widely used to model cancer and for carcinogen testing given their high susceptibility to carcinogen-induced tumors. Other also uses this for hybridoma production for immunological research.

A

AKR

AKR mice are useful in cancer, immunology, and metabolism research.

AKR

BALB/c

BALB/c mice are used for the production of monoclonal antibodies. Mammary tumor incidence is normally low, but infection with mammary tumor virus by fostering to MMTV+ C3H mice dramatically increases tumor number and age of onset. BALB/c mice develop other cancers later in life, including reticular neoplasm, primary lung tumors, and renal tumors.

BALB/cBy

BALB/cBy was separated from the BALB/c strain in 1935. Rare spontaneous myoepitheliomas arising from myoepithelial cells of various exocrine glands have been observed in the BALB/cBy substrain. BALB/cBy has a deletion in the Qa2 subregion of the murine MHC. A deficiency of Acads (acyl-coenzyme A dehydrogenase, short chain) leads to severe organic aciduria. BALB/cByJ develops a fatty liver upon fasting or dietary fat challenge and become hypoglycemic after an 18-hour fast.

BALB/c

BALB/c is susceptibility to developing the demyelinating disease upon infection with Theiler’s murine encephalomyelitis virus. The BALB/c substrain is also susceptible to Listeria, all species of Leishmania, and several species of Trypanosoma but is resistant to experimental allergic orchitis (EAO).

129P3 129X1/Sv 129S4/SvJae

Table 1.2 (Continued) Strain

Comment

Substrains

Comment

C3H

C3H mice are used in a wide variety of research areas including cancer, infectious disease, sensorineural, and cardiovascular biology research. C3H substrains at The Jackson Laboratory are homozygous for the retinal degeneration 1 mutation (Pde6brd1 ), causing blindness by weaning age.

C3H/He

A spontaneous mutation in Tlr4 occurred in C3H/HeJ at the lipopolysaccharide response locus (mutation in toll-like receptor 4 gene, Tlr4Lps-d) making C3H/HeJ mice more resistant to endotoxin. C3H/HeJ mice are highly susceptible to infection by Gram-negative bacteria such as Salmonella enterica. C3H/HeOuJ mice show high incidence of hepatoma. This strain does not carry mouse mammary tumor virus (MMTV), but virgin and breeding females may still develop some mammary tumors later in life.

C57BL/6 is the most widely used inbred strain. Although this strain is refractory to many tumors, it is a permissive background for maximal expression of most mutations. Five single nucleotide polymorphism (SNP) differences have been identified that distinguish C57BL/6J from C57BL/6N.

C57BL/6J

C57BL/6J is the first to have its genome sequenced. C57BL/6J mice are resistant to audiogenic seizures, have a relatively low bone density, and develop age-related hearing loss. C57BL/6J mice are also susceptible to diet-induced obesity, type 2 diabetes, and atherosclerosis. Macrophages from this strain are resistant to the effects of anthrax lethal toxin.

C57BL/6N

C57BL/6N is an NIH subline of C57BL/6. It was separated from C57BL/6J in 1951. This strain does not have the deletion in the Nnt gene that has been found in C57BL/6J.

CBA/Ca

CBA/Ca mice are commonly used for leukemogenesis research because this strain has a low spontaneous incidence of leukemia while myeloid leukemia can readily be induced. CBA/Ca mice carry viral proteins Mtv8, Mtv9, and Mtv14. Male CBA/Ca mice develop a mild adult-onset diabetes–obesity syndrome that is characterized by hyperglycemia, hyperinsulinemia, and insulin resistance. Unlike the CBA/J substrain, CBA/CaJ mice do not carry the retinal degeneration 1 allele (Pde6brd1 ) mutation, and CBA/CaJ mice are not histocompatible with the CBA/J.

C57BL/6

CBA

CBA was developed in 1920 from a cross of a Bagg albino female and a DBA male and selected for a low mammary tumor incidence.

C3H/HeOu

DBA

FVB

CBA

Unlike the CBA/Ca substrain, CBA mice is the only CBA substrain that carries the retinal degeneration 1 allele (Pde6brd1 ) mutation, which causes blindness by wean age. Renal tubulointerstitial lesions have been observed in this strain at a high frequency.

DBA is the oldest of all inbred strains of mice. In 1929–1930, crosses were made between substrains, and several new substrains were established, including substrains DBA/1 and DBA /2. DBA/1 and DBA/2 differ at least at the following loci: Car2, Ce2, Hc, H2, If1, Lsh, Tla, and Qa3. Differences between the substrains are probably too large to be accounted for by mutation and are probably because of substantial residual heterozygosity following the crosses between substrains.

DBA/1

DBA/1J mice are used as a model for rheumatoid arthritis: immunization with type II collagen leads to the development of severe polyarthritis mediated by an autoimmune response. DBA/1J mice show an intermediate susceptibility to developing atherosclerotic aortic lesions on an atherogenic diet. In response to challenge, DBA/1J mice develop immune-mediated nephritis characterized by proteinuria, glomerulonephritis, and tubulointerstitial disease DBA/2J mice show low susceptibility to developing atherosclerotic aortic lesions, high-frequency hearing loss, susceptibility to audiogenic seizures, development of progressive eye abnormalities that closely mimic human hereditary glaucoma, and extreme intolerance to alcohol and morphine.

FVB/NJ are commonly used for transgenic injection because of the prominent pronuclei in their fertilized eggs and the large litter size. FVB/NJ mice are homozygous for the retinal degeneration 1 allele of Pde6brd1, resulting in blindness by wean age.

FVB/N

DBA/2

8

1 Summary of Currently Available Mouse Models

1.3.4

Outbred Stocks

Outbred stocks are genetically undefined and intentionally not bred with siblings or close relatives, as the purpose of an outbred stock is to maintain maximum heterozygosity. One advantage of using outbred stocks is lower cost because outbred stocks have a relatively long lifespan, are resistant to disease, and have high fecundity. Regarding the nomenclature of outbred stocks, the common strain root is preceded by the Laboratory Code of the institution holding the stock. Example Hsd:NIHS, The NIH Swiss maintained by Harlan (Hsd) outbred stocks. 1.3.5

Closed Colony

A closed colony has limited genetic diversity. All mating occurs among the colony members, and no animals are introduced into the colony from outside the stock from generation to generation. Animals are produced by “rotation breeding” using the Harlem system, in which one male is mated with six to seven females. In terms of the nomenclature of outbred stocks, the common strain root is preceded by the Laboratory Code of the institution holding the stock. Example Jcl:ICR refers to the ICR maintained by CLEA Japan, Inc. (Jcl), closed colony. Closed colonies may be established to maintain a difficult mutation, where the desire is to maintain a reasonably uniform background, but poor mating performance prohibits use of sib-mating. Closed colony designations consist of the strain of origin and appropriately designated mutations (if applicable), followed by [cc] to indicate closed colony. Example BALB/cAnNTac-Bmp4tm1Blh [cc], a closed colony of mice originating from the BALB/cAnNTac inbred strain carrying the Bmp4tm1Blh targeted mutation. 1.3.6

Congenic Mice

Congenic strains are produced by repeated backcrosses to an inbred (background) strain for at least 10 generations, with selection for a particular marker from the donor strain. Marker-assisted breeding or marker-assisted selection breeding, also known as “speed congenic,” permits the production of congenic strains equivalent to 10 backcross generations in as few as five generations. At this point, the residual amount of unlinked donor genome in the strain is likely to be