The 129 mouse strain is an inbred line of laboratory mice whose genetic uniformity makes it a useful tool for studying the effects of specific genes and experimental variables. Its unique genetic characteristics and long history have made it particularly useful in genetics, immunology, and stem cell biology. These traits have also cemented its role in developing genetically modified animal models.
Historical Background and Lineage Development
The 129 mouse strain began in 1928 with biologist L.C. Dunn at Columbia University. He created the lineage by crossing mice from his coat color studies with a chinchilla-colored mouse stock. This initial cross laid the genetic foundation for the strain. An inbred strain involves mating closely related individuals for at least 20 consecutive generations to achieve a high degree of genetic uniformity.
In 1948, the mouse colony was sent to The Jackson Laboratory, a major center for mammalian genetics research, following a fire at its previous facility. This move was important for preserving and standardizing the strain for wider scientific use.
The work of Leroy Stevens at The Jackson Laboratory, starting in the 1950s, also influenced the strain’s development. Stevens was investigating the high rate of spontaneous testicular tumors in these mice. His research involved outcrossing 129 mice to other strains to study the genetic basis of these tumors, which inadvertently created new, distinct branches within the 129 family.
Understanding 129 Substrains
The term “129 mouse” describes a family of related, but genetically distinct, substrains. These substrains emerged as different colonies were bred independently, leading to genetic drift. This process results in small, cumulative genetic changes that differentiate one colony from another, impacting their physical and behavioral traits.
A standardized nomenclature was established to identify each substrain. The system uses a letter for the major lineage group, followed by a number for the particular substrain. The main lineages are 129P for “parental,” 129S for “steel,” and 129T for “teratoma,” reflecting their origins. An “X” designation is used for substrains found to be genetically contaminated.
Using precise nomenclature, such as 129S1/SvImJ or 129P3/J, is important for researchers because subtle genetic variations between substrains can influence experimental outcomes. For example, the “steel” (129S) lineage originated from crosses to study germ cells. In contrast, the “teratoma” (129T) lineage was bred for a high incidence of testicular tumors, making the choice of substrain a key part of experimental design.
Role in Genetic Engineering
The 129 mouse strain gained prominence for its role in the development of gene-targeting technology. This process allows scientists to create “knockout mice,” in which a specific gene has been inactivated or “knocked out.” This technique is used to understand the function of countless genes in both health and disease.
This technology relies on embryonic stem (ES) cells, which are cells from early-stage embryos that can develop into any cell type. The 129 strain was foundational because its ES cells could be readily isolated and maintained in a lab. Many widely used ES cell lines, such as the D3 and E14 lines, were derived from 129S2 and 129P2 substrains.
These 129-derived ES cells can be genetically modified in a petri dish to carry a desired mutation, such as a knocked-out gene. The modified cells are then injected into a developing mouse embryo from a different strain, often one with a different coat color to easily track the offspring. The resulting mouse is a chimera, composed of cells from both the original embryo and the modified ES cells. If the modified cells contribute to the germline, the genetic modification can be passed down to future generations.
The reliability of ES cell derivation made the 129 strain the model of choice for initial gene-targeting experiments. While techniques have evolved, the legacy of the 129 strain is present in thousands of genetically engineered mouse models. This research contributed to the 2007 Nobel Prize in Physiology or Medicine for discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells.
Distinct Physiological and Behavioral Traits
Mice of the 129 strain possess a unique set of inherent traits that can influence research findings. One of the most well-known is the high incidence of spontaneous testicular teratomas, a type of germ cell tumor. The rate of these tumors varies between substrains, from as low as 1-3% in parental (129P) lines to as high as 30% in some teratoma (129T) substrains.
Some 129 substrains also exhibit specific immunological characteristics. For instance, they can show a less effective recruitment of inflammatory cells in response to certain immune challenges. This trait can affect studies related to inflammation, infection, and autoimmune diseases. Researchers must account for this differing immune response when interpreting data.
Behaviorally, 129 mice often display lower levels of anxiety in certain experimental tests compared to other strains. However, some substrains show deficits in learning and memory tasks, such as impaired fear extinction. Additionally, some lines, like the 129P3/J substrain, are known to carry a mutation that leads to progressive, age-related hearing loss, which can be a confounding factor in behavioral studies that rely on auditory cues.