Colony Phenotyping

The objectives of phenotyping procedures are to cover the basics of observational assessment, gross necropsy examination, whole body and individual organ weights, clinical pathology assessments, and histological examination. As a first step in phenotyping mutant mouse lines, assessment of the colony as a whole unit is an important aspect. All mice should be observed at birth and at least once a week from birth until that time when the individual mouse is used for an experiment, euthanized, or dies naturally. Some phenotypes are readily seen or deducted, such as those mutations causing flaky skin (fsn)8 or those that are homozygous lethal. Defects in development may be seen at or within a few days of birth or may not be seen until much later in the life span. Researchers and technicians should be aware that any deviation from normal may be a phenotype, not only in individual mice but also throughout the transgenic line. Reproductive problems such as small litter size, elongated gestation or gestation cycles, and increased cannibalization may be due to genetic engineering rather than to environmental problems. Differences in hair quality, growth rate, skeletal structure or behavior between transgenic strains should be recorded and statistically evaluated to determine the effect of the transgene on the deviation. Colony records of the parameters in Table 10.1 will help to track the effect of a transgene or deletion mutation within a colony of genetically engineered mice.

The effect of background strain in determining the phenotype of transgenic mice is at many times a large one. Researchers should have a good understanding of the specific influences the background strain of their mice will have on the effects they see in the colony and in individual mice. Jackson Laboratories has a thorough and informative Web site listing many of the common diseases of the most popular inbred strains (www.jax.org). For example, C57BL/6 mice commonly exhibit ulcerative dermatitis and hydrocephalus. Knowing that these diagnoses are a result of the background strain and not the transgene will assist in true characterization of the mutant mice.

Another complicating factor in colony phenotyping is infectious disease. In a specific pathogen-free environment, all rooms should be routinely examined for infectious processes through the use of sentinel cages. Despite that precaution, disease can and will break through the protective barrier and cause infectious processes in genetically engineered mice. A routine plan of specific diagnostic procedures should be in place so that any deviation from the norm can be evaluated and the effects of infectious processes ruled out.

Table 10.1 Observational Assessments

Examine To Determine

Embryonic death Breeding efficiency

Litter size Fetal death

Birth weight and rate of growth Development

Hair growth

Eyes and ears open

Incisor eruption

Stand and walk

Physical exam for malformations Various clinical parameters

Coat and skin condition

Nasal or ocular discharge

Hemogram, serum chemistry profiles

Tumor development

Eating, drinking, grooming Simple behavioral patterns

Alertness, aggression

Activity level, exploration

Posture, climbing, locomotion

Righting, twitches, tremors, reflexes

Auditory startle, seizures

Stereotypic behaviors

Observational assessments, summarized in Table 10.1, should include general appearance, posture, and mobility. These features can be monitored with the help of trained animal care and technical staff on a consistent and intense basis. Daily reports should be made and weekly assessments compiled. Specific aspects should be tailored to the individual research plan. For example, aging studies can include hair graying and alopecia, body weights, muscle atrophy, lordokyphosis, dermal thickness, and subcutaneous adipose. For hair regrowth assessment, hair is shaved from a 2-cm-square area at the dorso-ventral back near the base of the tail. Regrowth is defined as the first appearance of hair in each of eight sections, designated by a transparent grid, in the shaved area. Aging ad lib-fed mice have been shown to have an extended hair regrowth time compared to calorically restricted mice.9

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