Pathology of genetically engineered and other mutant mice

Cover
Title Page
Copyright Page
Contents
List of Contributors
Preface and Acknowledgments
Chapter 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
Chapter 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
Chapter 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
Chapter 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
Chapter 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
Chapter 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
Chapter 7 Hematopoietic and Lymphoid Tissues
	Introduction
	Bone Marrow
	Lymphoid Tissues
		Primary Lymphoid Organs
		Secondary Lymphoid Organs
		Tertiary Lymphoid Organs
	Acknowledgments
	References
Chapter 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
		T-Cell Neoplasia
		Mature T-Cell Neoplasms
	Final Considerations
	Acknowledgments
	References
Chapter 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
		Naturally Occurring Lesions – Infectious and Parasitic
		Naturally Occurring Lesions – Noninfectiousor Parasitic
	References
Chapter 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
		Proliferative Skin Diseases
		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
Chapter 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)
		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
Chapter 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
	References
Chapter 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
		Pitfalls in Interpretation of Intestinal Carcinogenesis
	References
Chapter 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
Chapter 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
Chapter 16 Neuromuscular System
	Introduction
	General Guidelines
		Tissue Fixation
		Tissue Samples
	Histopathology
		Motor Neurons
		Peripheral Nerves
		Neuromuscular Junctions
		Mechanoreceptors
		Myocytes
	References
Chapter 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
	Thyroid Gland
		Anatomy, Histology, and Physiology
		Special Protocols
		Aging/Spontaneous Strain-Specific Lesions
		Genetically Engineered Mice
	Parathyroid Gland
		Anatomy, Histology, and Physiology
		Special Protocols
		Aging/Spontaneous Strain-Specific Lesions
		Genetically Engineered Mice
	Adrenal Gland
		Anatomy, Histology, and Physiology
		Special Protocols
		Aging/Spontaneous Strain-Specific Lesions
		Genetically Engineered Mice
	Pancreatic Islets
		Anatomy, Histology, and Physiology
		Special Protocols
		Aging/Spontaneous Strain-Specific Lesions
		Genetically Engineered Mice
	Pineal Gland
	References
Chapter 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
Chapter 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
Chapter 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
		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
		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
	References
Chapter 21 Nervous System
	Anatomy, Histology, and Physiology
		Neuroanatomic Localization
		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)
		-Synuclein Models
		LRRK2 Models
		Amyotrophic Lateral Sclerosis (ALS)
		Spinocerebellar Ataxias
		Huntington’s Disease (HD)
		Autoimmune
		Developmental:
		Epilepsy
		Traumatic Brain Injury and Post-Traumatic Epilepsy
		Malformation
		Neoplasia
	References
Chapter 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
		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
		Middle Ear Abnormalities
		Inner Ear Abnormalities
		Vestibular System Abnormalities
	References
Chapter 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 (CT)
		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
Index
EULA