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Группа авторов. Pathology of Genetically Engineered and Other Mutant Mice
Table of Contents
List of Tables
List of Illustrations
Guide
Pages
Pathology of Genetically Engineered and Other Mutant Mice
List of Contributors
Preface and Acknowledgments
1 Introduction to Mouse Pathology
The Use of Mice in Medical Research
Understanding Diseases Found in Mutant Animals
Mouse Pathology – Nomenclature
Mouse Genetic Nomenclature
Tumor Pathology
Immunohistochemistry (IHC), Scoring, Image Analysis, and Other Supportive Research Pathology Techniques
Publication of Erroneous Pathology Data: Inadvertent Fraud?
Overall Organization of the Book
Acknowledgments
References
2 The Mouse Online: Open Mouse Biology and Pathology Data Resources for Biomedical Research:
Introduction
FAIR Data Access and Databases of Databases
General Information on Inbred Laboratory Mice. Mouse Genome Informatics (http://www.informatics.jax.org)
MouseMine (http://www.mousemine.org/mousemine/begin.do)
Monarch (https://monarchinitiative.org)
Alliance of Genome Resources (https://www.alliancegenome.org)
Mouse Models of Human Cancer Database (MMHC, Formerly Mouse Tumor Biology Database) (http://tumor.informatics.jax.org/mtbwi/index.do)
Mouse Genome Informatics SNP Database (http://www.informatics.jax.org/snp)
Sanger Mouse SNP Database (https://www.sanger.ac.uk/sanger/Mouse_SnpViewer/rel‐1505)
Large Scale Mutagenesis. International Mouse Phenotyping Consortium (IMPC; https://www.mousephenotype.org)
MUTAGENETIX (https://mutagenetix.utsouthwestern.edu)
Background Strain Comparison Studies. Mouse Phenome Database (https://phenome.jax.org)
Mouse Pathology Image (Histopathology) Resources. Pathbase, the European Mouse Pathology Database (http://www.pathbase.net)
National Toxicology Program Neoplastic Lesion Atlas (https://ntp.niehs.nih.gov/nnl/index.htm)
Noah's Arkive, Charles Louis Davis, and Samuel Wesley Thompson Foundation for the Advancement of Veterinary and Comparative Pathology (http://noahsarkive.cldavis.org/cgi‐bin/show_image_info_page.cgi)
Organ/Disease Specific Resources
Bone Diseases: Skeletal Phenotyping of IMPC/KOMP Mice (http://www.bonebase.org)
Skin Diseases: Skinbase (http://eulep.pdn.cam.ac.uk/~skinbase/index.php)
GenitoUrinary Development Molecular Anatomy Project (GUDMAP) (https://www.gudmap.org)
Mouse Brain Atlas (https://developingmouse.brain‐map.org, https://mouse.brain‐map.org)
Atlas of Mouse Cardiovascular Development (https://www.devbio.pitt.edu/research/atlas‐mouse‐cardiovascular‐development)
Mouse/Human Disease Phenotype Databases
Online Mendelian Inheritance in Man (OMIM) (https://www.ncbi.nlm.nih.gov/omim)
Emouseatlas (https://www.emouseatlas.org/emap/home.html)
Finding Mouse Models
Use of Mouse Pathology Resources on Line; Citations, and Licenses
Acknowledgments
References
3 Mouse Genetic Nomenclature: The Underpinning of Mouse Genetics
Introduction
Why Use Standardized Nomenclature?
Inbred Mice
Hybrid Mice (F1 and F2)
Recombinant Inbred (RI) and Recombinant Congenic Mice
Collaborative Cross (CC) Mice
Congenic Mice
Consomic Mice
Conplastic Mice
Outbred Mice
Diversity Outbred (DO) Mice
Nomenclature for Normal and Mutated Genes
Spontaneous Mutations in Mice
Non‐engineered Induced Mutations
Chromosomal Aberration Nomenclature
Genetically Engineered Mice
Targeted, Endonuclease‐Mediated, Enhancer or Gene Trap, Transposon‐Induced, and Transgenic Mutations
Summary
Acknowledgments
References
4 Discovering and Validating Mouse Models of Human Diseases: The Cinderella Effect
Introduction
Basic Concepts of Defining a Mouse Model for a Human Disease
Large‐Scale Mutagenesis Projects to Discover New Mouse Models
From Human Polymorphism to Mouse Models
New Mouse Genetic Tools
Patient Derived Xenograft (PDX) Models
Acknowledgments
References
5 Embryos, Placentas, and Neonates
Introduction
Four‐Dimensional Anatomy of the Developing Mouse
Developmental Events in Embryos and Neonates
Developmental Events in Placentation
Technical Considerations for Pathologic Evaluation of Developing Mice
Noninvasive Imaging of Developing Mice
Anatomic Pathology Evaluation ofDeveloping Mice
Clinical Pathology Evaluation of Developing Mice
Pathologic Patterns in Mouse Embryos and Neonates
Pathologic Patterns in Mouse Placenta
Summary
References
6 Ciliopathies
Introduction
Motile Ciliopathies
Rhinosinusitis and Otitis Media
Hydrocephalus
Laterality Defects
Infertility
Sensory Ciliopathies
Cystic Kidney Diseases
Retinal Degeneration
Heart Defects
Skeletal Defects
Brain Malformations
Deafness
Anosmia
Obesity
Genetic Background Effects
References
7 Hematopoietic and Lymphoid Tissues
Introduction
Bone Marrow
Lymphoid Tissues
Primary Lymphoid Organs
Thymus
Secondary Lymphoid Organs. Lymph Nodes
Mucosa‐Associated Lymphoid Tissues
Spleen
Milky Spots
Tertiary Lymphoid Organs
Acknowledgments
References
8 Mouse Hematolymphoid Neoplasms
Introduction and Overview of the Classification of Leukemias and Lymphomas in the Mouse
Nonlymphoid Hematopoietic Neoplasms in Mice. Myeloid Leukemia (Granulocytic Leukemia, Myelogenous Leukemia, and Myelocytic Leukemia)
Myelomonocytic Leukemia
Monocytic Leukemia
Erythroid Leukemia
Megakaryocytic Leukemia
Mast Cell and Basophil Leukemia
Myeloid Proliferations (Nonreactive)
Bone Marrow, Spleen, and Other Tissues
Myeloid Dysplasia
Nonlymphoid Hematopoietic Sarcomas. Myeloid Sarcoma
Histiocytic Sarcoma
Dendritic Cell Tumors/Histiocytosis
Mast Cell Neoplasms
Lymphoid Neoplasms. Overview of Lymphoid Neoplasm Classification
B‐Cell Neoplasms. B‐Cell Lymphoblastic Lymphoma/Leukemia (LBL)
Small B‐Cell Lymphoma/Leukemia
Splenic Marginal Zone Lymphoma
Mucosa‐Associated Lymphoid Tissue Lymphoma
Mantle Cell Lymphoma
Plasma Cell Neoplasms
Follicular Lymphoma
Diffuse Large B‐Cell Lymphoma (DLBCL)
Diffuse High‐Grade Blastic B‐Cell Lymphoma
Natural Killer B‐Like (NKB) Cell Lymphoma
T‐Cell Neoplasia. T‐Cell Lymphoblastic Lymphoma/Leukemia (T‐LBL)
Mature T‐Cell Neoplasms. Small T‐Cell Lymphoma (STL)
Peripheral T‐Cell Lymphoma, NOS
Anaplastic Large Cell Lymphoma
Granular Lymphocyte Lymphoma/Leukemia
Cutaneous T‐Cell Lymphoma (CTCL)
Thymus Neoplasms
Final Considerations
Acknowledgments
References
9 Immunodeficient and Humanized Mice
Introduction
Nude Mice
Prkdcscid, Rag1 and Rag2‐Deficient,and Lystbg Mice
NOD‐Prkdcscid Mice
IL‐2RG‐Deficient Mice
Uses of Immunodeficient Mouse Models. Xenotransplants of Solid and Hematopoietic Human Patient‐Derived Tumors or Neoplastic Cell Lines
Immunologic Reactions AgainstTransplanted Tumors
Humanized Mice
Common Lesions in Immunodeficient Mice. Experimentally Induced Lesions. Xenogeneic GVHD
Epstein–Barr Virus Induced Lymphoma
Posthematopoietic Transplant Bone Marrow Failure
Naturally Occurring Lesions – Infectious and Parasitic. Recently Recognized and Emerging Diseases in Immunodeficient Mice
Mouse Kidney Parvovirus (MKPV, aka Murine Chapparvovirus – MuCPV)
Clostridioides difficile
Burkholderia spp
Candida spp
Demodex musculi
Historically Recognized Pathogens
Naturally Occurring Lesions – Noninfectiousor Parasitic
References
10 Skin, Hair, and Nails
Introduction
Normal Anatomy and Embryology of Mouse Skin, Hair, and Nails
Practical Guidelines for the Biological Characterization of a New Mutation
Categories of Disease of the Skin and Adnexa. Hair Color (Pigmentation) Mutations
Sebaceous and Eccrine Gland Defects and Scarring Alopecias
Hair Follicle Cycling and Structural Defects of Hair Shafts. Hair Cycle
Hair Texture Abnormalities and Hair Shaft Structural defects
Proliferative Skin Diseases
Psoriasiform Dermatitis
Ichthyosiform Dermatoses
Autoimmune Skin Diseases
Skin Cancers. Cancer‐like Epidermal Response to Injury (Pseudoepitheliomatous/Pseudocarcinomatous Hyperplasia)
Spontaneous Nonmelanoma Skin Cancers in Mice
Two‐stage Chemical Carcinogenesis
UV Light‐Induced Carcinogenesis
Papillomaviruses
Mouse Models of Melanoma
Bullous and Acantholytic Skin Diseases: Pemphigus, Pemphigoid, and Epidermolysis Bullosa
Structural and Growth Defects in Nails
Summary
Acknowledgments
References
11 Mammary Gland
Introduction
Anatomy, Histology, and Biology of Mouse Mammary Glands
Mammary Gland Biology
Pathology of the Mammary Gland
Neoplastic Progression
Mammary Tumor Invasion and Metastases
Genetic Engineering of Mouse Mammary Gland
Promoters
Oncogenes and Tumor Suppressors
Oncogene Addiction and Nononcogene Addiction (NOA)
Metaplasia
Host and Environmental Factors
GEM Mammary Tumors. How to Evaluate a Model
Pathology. Terminology, Classification, and Description
Genotypes Predict Phenotypes
Mouse Comparisons with Human (Table 11.1)
GEM MIN
Metastasis
Metaplasia
Important Techniques for the Evaluation of the Mammary Gland
Preparation of Mammary Gland Whole Mounts
Preparation of Lung Whole Mounts
Fixation and Processing
Immunohistochemistry (IHC)
Mammary Gland Transplantation
Host Response
Case Study: 129S6/SvEvTac‐Stat1tm1Rds Mammary Biology and Tumorigenesis (Figures 11.2, 11.7, and 11.10)
Mammary Growth and Development
Summary
Internet Resources
References
Notes
12 The Respiratory Tract
Introduction
The Upper Respiratory Tract. Anatomy and Histology
Developmental Defects
Pathology of the Nose
The Lung. Anatomy and Histology
Lung Necropsy and Histology Protocols
Immunohistochemistry of the Lung
Lung Development
Congenital Diaphragmatic Hernia
Approaches to Phenotyping the Respiratory System
Pathology of the Lung
Spontaneous Lung Lesions in Mice
Disease Models. Scoring of Lung Lesions
Infectious Disease Models
Mouse Models of Human Pulmonary Genetic Disorders
Asthma
Pulmonary Fibrosis Models
Lung Tumors
Lung Tumors in Mice
References
13 The Gastrointestinal Tract
Introduction
Stomach. Anatomy and Histology
Necropsy, Trimming, and Embedding Protocol
Pathology of the Human Stomach
Pathology of the Mouse Stomach
Genetically Engineered Mice
Neoplasms and Other Proliferative Lesions
Cystic Proliferative Lesions in the Stomach and Intestine
The Small and Large Intestine. Normal Anatomy and Histology
Necropsy and Pathology Protocol
Pathology of the Human Intestine
Histopathology of the Mouse Intestine
Mouse Models of Inflammatory Bowel Diseases and Related Diseases (Colitis Models)
Colitis Necropsy and Tumor Histopathology Protocols
Microbiota and Colitis
Human Intestinal Neoplasia
Mouse Models of Intestinal Cancer
Intestinal Tumor Pathology
Other Intestinal Tumors
Specific Intestinal Tumor Models
ApcMin/+ and Related Models
Mismatch Repair Deficiency Models
Models with Alterations in Tgfb1 Signaling
Immunodeficiency Models
Pitfalls in Interpretation of Intestinal Carcinogenesis
Regeneration Adjacent to Ulcer
References
14 Cardiovascular System
Mouse Anatomy, Histology, and Physiology
Heart
Cardiac Conduction System
Resident Immune Cells of the Heart
Circulatory System: Vasculature
Elastic Arteries
Muscular Arteries and Veins
Special Necropsy Organ Protocols
Detection of miRNAs of Cardiovascular System
Aging/Spontaneous Strain Specific Lesions
Osseous Metaplasia (Os Cordis)
Polyarteritis Nodosa
Epicardial/Myocardial Mineralization
Atrial Thrombosis
Hyaline Arteriolosclerosis
Myxomatous Degeneration of the Cardiac Valves (Endocardiosis)
Bicuspid Aortic Valve (BAV)
Melanosis
Aortitis
Opportunistic Bacteremia/Endocarditis/Myocarditis in Immune‐Incompetent Mice
Neoplasia
Genetically Engineered Mice (GEMs) Models of Heart and Vessel Disease
Septation
Aortic Stenosis
Cardiomyopathies
Hypertrophic Cardiomyopathy
Dilated Cardiomyopathy
Arrhythmogenic Cardiomyopathy
Other Cardiomyopathies
Restrictive Cardiomyopathies
Lysosomal Storage Diseases
Markers of Cardiovascular Disease in Other Organs
Aorta
Aneurysm and Dissection
Tortuosity
Systemic hypertension
Vasculitis
Atherosclerosis
Summary
Acknowledgments
References
15 Liver and Pancreas
Liver
Anatomy, Histology, and Physiology
Special Necropsy Organ Protocols
Aging/Spontaneous Strain Specific Lesions
Genetically Engineered Mice (GEM)
Genetically Engineered Mouse Models for Liver Diseases
Mouse Models of Nonneoplastic Liver Diseases
Histogenesis of HCC and Other Hepatic Tumors
Induction of Mouse Liver Tumors
Pathways to Human HCC
Humanized Mouse Liver Models for Liver Diseases
Genetically Edited Mouse Models for Liver Disease
Exocrine Pancreas. Anatomy and Histology
Necropsy, Trimming, and Embedding
Aging/Spontaneous Strain‐Specific Lesions
Pathology of the Human Pancreas
Neoplasms and Other Proliferative Lesions
Familial and Hereditary Pancreatic Cancer
Risk Factors of PDAC
Genetically Engineered Mice
GEM for Inflammatory Lesions of the Pancreas
GEM for PDAC
References
16 Neuromuscular System
Introduction
General Guidelines
Tissue Fixation
Tissue Samples
Histopathology
Motor Neurons
Peripheral Nerves
Neuromuscular Junctions
Mechanoreceptors
Myocytes
Sarcolemma
Sarcoplasmic Reticulum and Transverse Tubules
Myofibrils
Mitochondria
Autophagy
Mixed Myopathies
References
17 Endocrine System
Overview
General Phenotypic Considerations for the Endocrine System
Pituitary Gland. Anatomy, Histology, and Physiology
Special Necropsy Organ Protocols
Aging/Spontaneous Strain‐Specific Lesions
Genetically Engineered Mice. Hypopituitarism
Hyperpituitarism
Craniopharyngiomas
Thyroid Gland. Anatomy, Histology, and Physiology
Special Protocols
Aging/Spontaneous Strain‐Specific Lesions
Genetically Engineered Mice. Hypothyroidism
Hyperthyroidism
Neoplasms of Thyrocytes
Thyroid C Cell Neoplasms
Parathyroid Gland. Anatomy, Histology, and Physiology
Special Protocols
Aging/Spontaneous Strain‐Specific Lesions
Genetically Engineered Mice. Hypoparathyroidism
Hyperparathyroidism
Adrenal Gland. Anatomy, Histology, and Physiology
Special Protocols
Aging/Spontaneous Strain‐Specific Lesions
Genetically Engineered Mice. Adrenal Insufficiency
Adrenocortical Hyperplasia and Tumors
Tumors of the Adrenal Medulla
Pancreatic Islets. Anatomy, Histology, and Physiology
Special Protocols
Aging/Spontaneous Strain‐Specific Lesions
Genetically Engineered Mice. Diabetes Mellitus
Islet Neoplasia
Pineal Gland
References
18 Kidney and Urinary Bladder
Introduction
Mouse Kidney Development, Anatomy, and Histology
Pathology of the Mouse Kidney
Characterization of Kidney Disease Phenotypes in Mice: Clinical Pathology
Glomerular Numbers
Preparation of Kidneys for the Histopathology
Morphologic Examination
Glomerular Diseases
Tissue Assessment of Immunologic Disease in Mouse Models
Mouse Models of Human Glomerular Diseases
Pathology and Scoring of Mouse Renal Glomerular Lesions
Systemic Lupus Erythematosus
Virus‐Associated Kidney Diseases
Renal Tubular Disease
Human Genetic Disorders of Tubules
Mouse Models of Cystic Kidney Disease
Spontaneous Tubular Lesions of Mice
Renal Tumors
Urinary Bladder: Anatomy and Histology
Fixation and Trimming of Urinary Bladder
Urinary Bladder Physiology
Urolithiasis
Urinary Bladder Neoplasia
Conclusion
References
19 Female Reproductive System
Embryology and Normal Anatomy of Organs of the Female Reproductive Tract. Embryology
Normal Anatomy and Histology
Normal Estrous Cycle Changes
Biological Characterization of a New Mutation of Female Reproductive Tract
Collection of the Female Reproductive Tract Organs (Ovary/Oviduct/Uterus/Uterine Cervix and Vagina)
Special Stains for the Ovaries, Uterus, Cervix, and Vagina
Spontaneous or Induced Mutant Phenotypes of the Gonads and Receptors
Sex Steroid Receptor Deficient Mice
Mutants Affecting Pituitary Function
Mutants with Defective Steroidogenesis
Growth Factor Mutations
Mutants with Germ Cell Aplasia
Mutants with Changes in Germ Cell Apoptosis
Phenotypes of Gonadal Neoplasia
Miscellaneous Models with Reproductive Tract Phenotypes
Models of Diseases Affecting the Female Reproductive Tract. Models of Polycystic Ovarian Syndrome (PCOS)
Models of Ovarian Cancer
Models of Endometriosis
Models of Endometrial Cancer
Models of Uterine Fibroids
Models of Cervical Cancer
Aging/Spontaneous Strain Specific Lesions
Acknowledgments
References
20 Male Reproductive System
Introduction
Male Reproductive System
Accessory Sex Glands. Anatomy and Histology
Special Necropsy and Trimming Protocols
Preputial Glands. Necropsy and Trimming Protocols
Anatomy and Histology
Pathology of Preputial Glands
Bulbourethral Glands (Cowper's Glands) Anatomy and Histology
Pathology of Bulbourethral Glands
Genetically Engineered Mice
Ampullary Glands
Periurethral Glands (Glands of Littré)
Genetically Engineered Mice
Seminal Vesicles. Anatomy and Histology
Pathology of Seminal Vesicles
Genetically Engineered Mice
Prostate. Anatomy and Histology
Special Necropsy and Trimming Protocols
Special Histochemical Stains and Immunohistochemical Markers
Pathology of Prostate Glands
Genetically Engineered Mouse Models
Pathology and Classification of Lesions of the Prostate in Genetically Engineered Mouse Models
Epithelial Hyperplasia
Mouse Prostatic Intraepithelial Neoplasia (mPIN)
Adenocarcinoma
Sarcomatoid Carcinoma
Neuroendocrine Carcinoma
Specific Prostatic Tumor Models
Models with Alterations in PTEN/AKT Signaling
Models with Alterations in MYC Signaling
Models with Alterations in ERG Signaling
Models with Alterations in Fibroblast Growth Factor (FGF) Signaling
Models with Alterations in Androgen Receptor (AR) Signaling
Models with Alterations in TGF‐b Signaling
SV40 T‐antigen
Cyclin Dependent Kinase Inhibitor 2A (CDKN2A)
Testes and Epididymis. Anatomy, Histology, Physiology
Special Necropsy and Trimming Protocols
Aging and Spontaneous Strain‐Specific Lesions. Testis
Degeneration, Atrophy, and Germ Cell Depletion
Tubular Necrosis
Miscellaneous Changes. Mineralization
Amyloid
Pigment
Mononuclear Aggregates
Epididymis
Genetically Engineered Mouse Models of Male Infertility. Histopathology Classification and Mechanisms of Action
Pathology of the Testis in Infertile GEM
Seminiferous Tubule Degeneration/Atrophy
Spermatogenesis Arrest and Spermiation Defects
Multinucleated Spermatids; Symplasts
Germ Cell Exfoliation
Tubule and Sertoli Cell Vacuolation
Tubular Dilation
Primary Ciliary Dyskinesia (Immotile Cilia Syndrome)
Leydig Cell Abnormalities
Pathology of the Epididymis in Infertile GEM
Neoplasms of the Testis
Sex Cord‐Stromal Tumors. Leydig Cell Tumors
Sertoli Cell Tumors
Granulosa Cell Tumors
Germ Cell Tumors. Seminoma
References
Note
21 Nervous System
Anatomy, Histology, and Physiology
Neuroanatomic Localization
Specific Signs Related to Neuroanatomic Localization. Prosencephalon
Brainstem
Cerebellum
Spinal Cord
Necropsy Protocols
Histological Artifacts
Aging/Spontaneous Strain Specific Lesions
Genetically Engineered Mice (GEM) Disease Models: Degenerative
Alzheimer's Disease (AD)
Amyloid Plaques/Models of Amyloid Pathology
Neurofibrillary Tangles and Neurodegeneration/Models of Tau Pathology
Mouse Factors
Online Resources
Parkinson’s Disease (PD)
α‐Synuclein Models
LRRK2 Models
Other Genetic Models: Prkn, Pink1, and Park7 (Synonym DJ‐1)
Pharmacologic and Toxic Models
Online Resources
Amyotrophic Lateral Sclerosis (ALS)
Online Resources
Spinocerebellar Ataxias
Huntington’s Disease (HD)
Autoimmune. Experimental Allergic Encephalitis
Developmental: Lysosomal Storage Diseases
Epilepsy
Traumatic Brain Injury and Post‐Traumatic Epilepsy
Malformation
Neoplasia
References
22 Eye and Ear
Anatomy, Histology, and Physiology of the Eye
Optic Nerve
Lids and Ocular Adnexa
Gross Phenotyping Screen
Optic Function Evaluations
Posterior Eye Examination
Photoreceptor Function Evaluations
Special Necropsy Organ Protocols. Collection
Fixation and Decalcification
Tissue Processing and Sectioning – Paraffin Embedded Samples
Interpretation of Eye Sections
Description/Lesions of the: Globe (as a Whole)
Ocular Adnexa and Eyelids
Anterior Segments Including the Conjunctiva, Cornea, Iris, and Ciliary Body
Lens
Posterior Segments in Cluing the Vitreous, Choroid, Retina, and Optic Nerve
Neoplasia
Spontaneous Mutations Associated with Strain‐Specific Eye Lesions
Genetically Engineered and Mutant Mice (GEMs)
Anatomy, Histology, and Physiology of the Ear
Phenotyping Screen
Gross Necropsy and Trimming
Embryology
Histology
Aging/Spontaneous Strain Specific Lesions
Abnormalities in Genetically Engineered Mice. External Ear Abnormalities
Middle Ear Abnormalities
Inner Ear Abnormalities
Vestibular System Abnormalities
References
23 Bones and Teeth
Introduction
Bone
Bone Structure
Bone Cells
Differences Between Mouse and Man
Phenotyping Mouse Bone. Histomorphometry
Whole Mounts
Dual X‐ray Absorptiometry (DXA)
Microcomputed Tomography (μCT)
Additional X‐ray‐Based Imaging Techniques
Biomechanical Testing
Histology
Diseases of Bone. Fibro‐osseous Lesions
Diseases of High Bone Mass
Diseases of Low Bone Mass
Biomineralization Defects
Osteogenesis Imperfecta
Cartilage Defects
Teeth
Abnormal Tooth Numbers/Shapes
Enamel Defects
Dentin Defects
Incidental Lesions
Acknowledgments
References
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