Review ArticleMouse phenotyping
Section snippets
Core facility
Model organisms like the mouse are important tools to learn more about gene function in man. Over the last 20 years many mutant mouse lines have been generated by different methods such as ENU mutagenesis, constitutive and conditional knock-out approaches, knock-down, introduction of human genes, and knock-in techniques, thus creating models which mimic human conditions. Due to pleiotropic effects, one gene may have different functions in different organ systems or time points during
Dysmorphology, bone and cartilage
The skeleton is the third largest organ system in the human body and consists of bone and cartilage. Musculoskeletal diseases including rheumatoid arthritis, osteoarthritis, osteoporosis, major limb trauma, and spinal disorders are the most frequent cause of physical disability for people in developed countries. The etiology and pathological basis of skeletal diseases are diverse in nature. Studies of naturally occurring and engineered mutant mice have led to a dramatic increase in the
Behavioral phenotyping
Animal behavior can be viewed as the outward manifestation of an orchestrated and complex functioning of the central nervous system (CNS) and of its interactions with the internal and external environment. In the context of functional mouse genetics, behavioral phenotyping methods are applied to detect CNS dysfunctions that are relevant to human neuropsychiatric disorders such as post-traumatic stress disorder, other anxiety disorders, depression, schizophrenia, autism, attention-deficit
Neurological phenotyping
Neurological disorders are a major health problem. Neurodegenerative diseases like Parkinson’s disease, amyotrophic lateral sclerosis or Huntington’s disease are still in need of suitable therapeutic approaches. Animal models provide a useful tool for research into human diseases and their phenotypic characterization is a prerequisite for the analysis of assignable attributes of human disease to respective mouse models as well as for the evaluation of therapeutic benefits [29].
Neurological
Cataract quantification in the mouse using the Scheimpflug imaging technique
The mouse is a well-established model for studying congenital eye disorders with a variety of existing test systems profiting from the relatively easy access to this organ. Mutants for retinal disorders have been characterized mainly by funduscopy or electroretinography [33], by the optokinetic drum for retinocortical pathways [34], [35], [36], [37], [38], [39] and by slit lamp microscopy for opacities in cornea and lens [37], [38], [40]. However, additional techniques are required for more
Nociception
Acute pain, a somatosensory signal of impending or present tissue injury, elicits avoidance, defense or escape behaviors in mice. These behaviors are used in an experimental setting to assess the animals’ perception of the intensity of defined thermal, mechanical, or chemical nociceptive stimuli. Chronic pain is a pathological condition that results in changes of the somatosensory system so that pain thresholds are reduced (hyperalgesia) or pain even occurs without any nociceptive stimulus
Phenotypic analysis of mouse models with impaired kidney function using metabolic cages
The aim of the primary Clinical–Chemical Screen of the German Mouse Clinic (GMC) is the detection of genotype-related effects on clinical–chemical and hematological parameters by means of suitable approved laboratory diagnostic tools [52], [53], [7].
Alterations detected in plasma urea, creatinine or protein levels as well as changes in electrolyte homeostasis and also increased cholesterol levels may be due to impaired kidney function in the respective mouse line [54], [55], [56], thereby
Immunological phenotyping of peripheral mouse blood
The measurement of leukocyte populations in peripheral blood by the Immunology unit at the German Mouse Clinic is part of multi-screen serial studies, performed on the living animal. The flow cytometric analysis which is based on two 10-parameter staining panels, covering markers for the main lineages: B cells, T cells, granulocytes, NK cells, and further subsets (for further information see: [7] requires only a small amount of blood. Despite this obvious advantage, there are several
High-throughput strategies for the detection of allergy prone mutant mice
IgE-mediated atopic disorders such as allergic asthma, allergic rhinitis, and atopic dermatitis are now considered as environmentally and exposure driven immune disorders leading to the expression of various clinical phenotypes in individuals with defined genetic risk profiles [59]. Understanding the complex genetic program that leads to the precipitation of such phenotypically distinct diseases in atopy will be essential for the development of new diagnostic and therapeutic approaches to
Mouse phenotyping by metabolomics
Metabolomics is a very fast expanding research field for the phenotyping of biological samples involving an unbiased characterization approach. Especially, morphologically not visible phenotypes can be specifically determined if concentrations of independent metabolites are quantified [67], [68], [69]. Very early metabolic responses to pharmacological treatment in mouse can be unequivocally detected [70]. Two main approaches are followed in metabolomics: (1) targeted metabolomics, where chosen
Energy metabolism
Both diseases of high public health impact (e.g. obesity or diabetes) and a broad spectrum of medical conditions are directly or indirectly related to malfunctional energy balance regulation. This explains why the identification of disturbed energy homoeostasis is one of the key goals of our mouse phenotyping program. Primary metabolic phenotypes are characterized by an imbalance between energy intake (affected by food intake, rate of food processing, intestinal nutrient and energy uptake) and
Diabetes Screen
Impaired Glucose Tolerance (IGT) and elevated fasting plasma glucose concentrations in a mouse mutant – as e.g. determined in the GMC Clinical Chemistry and Metabolism Screens – might result from an (1) impaired capacity of pancreatic β-cells to adequately secrete insulin in response to glucose and/or (2) insulin resistance The latter is defined as the decreased sensitivity or responsiveness of target tissues such as liver, skeletal muscle, adipose tissue, brain, or heart to the metabolic
Cardiovascular phenotyping
Since Cardiovascular diseases (CDV) remain one of the most prevalent disorders and a leading cause of death, the comprehensive/efficient cardiovascular phenotyping of mutant mouse models remains an ongoing task for the identification of novel candidate disease genes. Finding suitable animal models for these often complex diseases provides opportunities for new therapeutic approaches and for investigations of the underlying pathogenesis.
A primary first-line screening for cardiovascular
Respiratory Function Screen
Lung diseases are among the leading causes of death worldwide [101], [102], [103]. Major contributors are chronic obstructive pulmonary disease (COPD) and asthma, determined by inherited and environmental factors. Despite increased research effort and the development of suitable animal models, a substantial knowledge gap still remains concerning gene-phenotype interactions. To improve our understanding of the interplay of genetic variants and to help in developing new therapeutic strategies in
Molecular phenotyping
Microarray-based gene expression profiling as an approach to molecularly phenotype organs of MMLs at the transcript level is currently not part of the EMPReSSslim protocol, since it is deemed too labor and cost-intensive. However, by combining the systematic collection of a set of organs with a biased selection of organs for gene expression analyses based on knowledge about gene functions, we have been able to demonstrate that the primary molecular phenotyping screen of the GMC is at least as
Pathology
Genetically engineered mice have become indispensable tools for cancer research, and for the identification of genes involved in human diseases. A complete phenotyping of a mouse model is a challenge for which most research laboratories are not prepared. The GMC was designed to offer a large-scale, standardized and comprehensive phenotype analysis of mouse mutants to the scientific community. The pathology screen within the GMC plays a pivotal role in the final analysis of mouse models. The
Acknowledgments
We would like to thank Reinhard Seeliger, Miriam Backs, Nicole Boche, Sabrina Bothur, Ralf Fischer, Michaela Grandl, Tamara Halex, Sabine Holthaus, Elfi Holupirek, Constanze König, Maria Kugler, Albert Langer, Katrin Laube, Astrid Markert, Jacqueline Müller, Elenore Samson, Sandra Schädler, Florian Schleicher, Daniela Schmidt, Waldemar Schneider, Ann-Elisabeth Schwarz, Anett Seelig, Bettina Sperling, Waltraud Stettinger, Lucie Thurmann, Susanne Wittich, Anja Wohlbier and Claudia Zeller as well
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