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Tools for genetics and genomics: Specially bred and genetically engineered mice

Tools for genetics and genomics: Specially bred and genetically engineered mice
Literature review current through: Jan 2024.
This topic last updated: Oct 04, 2023.

INTRODUCTION — Laboratory mice are among the most widely used model systems in biomedical research.

This topic discusses a subset of mouse resources and methods that support common and important research that is largely confined to mice. These include transgenic, knockout, knock-in, lineage tracing and pathway reporting strains, and immunodeficient and humanized mice.

Many other genetically engineered and specially bred mice are foundational for biomedical research but are beyond the scope of this document. Interested readers can find links to freely available educational materials curated by the Jackson Laboratory.

Other model systems for studying human disease are discussed separately (eg, yeast, worm, fruit fly, zebrafish). (See "Tools for genetics and genomics: Model systems".)

TECHNICAL UNDERPINNINGS AND GENOME EDITING — The fundamental technology at the core of most genetically engineered mice is the ability to introduce foreign DNA into pluripotent recipient cells. In practice, this is accomplished either by direct microinjection of DNA into a fertilized egg (picture 1), or by transfection into mouse embryonic stem (ES) cells (pluripotent cells that can give rise to all tissues, including the germline) [1-3]. (See "Overview of stem cells", section on 'Embryonic stem (ES) cells'.)

ES cells can be grown in culture and subjected to transfection and selection in the same manner as other cultured cells. ES cells shown to harbor the desired construct are then injected into mouse blastocysts to yield chimeric embryos. The blastocysts can then be implanted into foster mothers and the pregnancy carried to term.

Notable technical advances have occurred in genome editing, including the use of zinc finger nucleases, transcription activator-like effector nucleases (TALENs), and the CRISPR/Cas system [4]. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Gene editing'.)

These tools have greatly reduced the time and expense of creating knockout and knock-in animals. (See 'Knockout mice' below and 'Knock-in mice' below.)

TYPES OF GENETICALLY ENGINEERED MICE

Transgenic mice — Transgenic mice are those into which foreign DNA has been incorporated into the genome. According to this broad definition, all types of genetically engineered mice are transgenic. In a narrower sense, transgenic mice have an "extra" gene introduced to accomplish any of several experimental objectives:

To correct pathology caused by mutation, thus proving that the transgene complements the preexisting mutation [5]

To introduce a reporter gene under specified genetic control to identify tissues and times at which the included control is active [6-8]

To introduce an abnormal gene, thus creating a disease model [9]

Simple transgenics, in which no attempt is made to target the construct to a specific site in the genome, can be generated by microinjecting DNA directly into one of the pronuclei of fertilized eggs in vitro. Surviving blastocysts are implanted into foster mothers and pups analyzed for presence of the transgene.

Knockout mice — In contrast to simple transgenic animals, knockout mice depend upon successful gene targeting to disrupt a specific gene [10]. This is achieved by using genetic selection to enrich transfected ES cells for successful targeting.  

The motivation for doing this is to study the consequences of loss of function of the targeted gene directly in vivo. In contrast to experiments using cultured cells, the knockout allows the consequences of target gene disruption to be evaluated in the context of whole-organism physiology. In this setting, it is possible to study physiological adaptation to the knockout and discover effects in tissues in which pathology might not have been suspected a priori. Comparison and contrast among knockout phenotypes for related target genes help to identify both the unique and redundant functions of their products.

Knock-in mice — Knock-in mice are theoretically similar to knockout mice, with the important difference that an altered rather than a null version of the target gene is substituted for the naturally occurring allele. Knock-in technology allows examination of the effects of different mutations on the same gene. This is particularly informative if the mutations thought to cause human disease result in gain of function rather than loss of function (eg, oncogenes) or if the goal is to investigate a mutant in a single tissue. (See 'Conditional systems' below.)

Conditional systems — Some gene disruptions are lethal or lethal too early in development to allow fruitful investigation of their consequences. Alternatively, sometimes an experiment seeks to define the role of a gene's expression within a single tissue or cell type. A variety of methods have been developed to address this class of problems.

Inducible promotors – Modulating transgene expression can be achieved by placing the transgene under the transcriptional control of an inducible promoter. The bacterial tetracycline resistance operon provides such a reagent system [11-13]. The investigator can then regulate transgene expression by titrating administration of tetracycline to the transgenic animals.

Tissue-specific knockouts – A strategy by which knockout expression can be restricted is generation of tissue-specific knockouts. This approach exploits the ability of bacteriophage P1 Cre recombinase to mediate site-specific recombination at specific short sequence elements called loxP sites [14]. Two engineered mice must be produced to carry out such an experiment. One construct introduces the loxP sites into the target gene, flanking sufficient DNA so that its deletion will achieve the desired loss of target gene activity. The second construct, which can be a simple transgene, introduces a functional gene for Cre recombinase driven by a tissue-specific promoter. Mice homozygous for the target gene construct are then mated to mice harboring the tissue-specific Cre construct. Offspring receiving the construct (expected to be 50 percent of the progeny) will express Cre recombinase in a tissue-specific manner, leading to excision of the portion of the target gene flanked by the loxP sites, thus knocking out the gene in that tissue exclusively (figure 1) [15,16].

Collaborative projects in North America and in Europe have developed conditional knockout alleles for thousands of genes [17-20].

Chimeric systems – The extraembryonic tissues are important in early developmental steps including gastrulation. One group developed a method by which early embryos can be tetraploidized, and chimeric embryos produced from tetraploidized embryos and cultured ES cells [21,22]. Under these conditions, the tetraploid cells give rise exclusively to extraembryonic tissue, while the diploid ES cells produce all of the embryo proper. This approach allows investigators to overcome some early developmental defects, thus allowing later functions of the disrupted gene to be studied [23,24].

Reporter mice — A common application of transgenic technology is to introduce an easily assayed reporter. Early work used b-galactosidase as the reporter molecule, which can be used to generate a blue histochemical dye specifically in tissues where the gene is expressed, and targeted a locus, Rosa26, that allows ubiquitous expression and whose disruption is phenotypically silent [25]. Expression is restricted by use of a tissue-specific or lineage-specific Cre construct. (See 'Conditional systems' above.)

Subsequent work has increasingly relied on fluorescent reporters which allow high resolution and obviate the need for histochemical processing [26-31].

Lineage tracing is a common application invoked by using a tissue-specific or lineage-specific Cre in combination with a reporter construct [32]. Its use to validate tissue-specificity of Cre activity is considered best practice [33]. Lineage tracing with more elaborate reporters is also used to perform dynamic studies [8]. Examples include:

Investigating the healing of injured glomeruli [34]

Demonstrating the existence of functionally distinct endosteal and periosteal mesenchymal stem cells [35]

Reporter mice can also identify the anatomic sites at which specific biologic pathways are active. As an example, the TOPGAL mouse expresses beta-galactosidase at sites of canonical Wnt signaling [36]; this allows investigators to identify the tissues in which the pathway is active. In a 2022 study, combinatorial expression of eight signaling pathways was proposed to account for all developmental cell fates [37]

Humanized immunodeficient mice — In spite of their many strengths as a model organism, mice cannot adequately recapitulate all the features of human biology. These limitations are particularly evident in studies of immune function, transplantation, infectious diseases, and tumor biology. In order to overcome these limitations, investigators have developed the ability to engraft human cells and tissues into mice. These so-called humanized mice rely on exploiting immunodeficient mice, which have long served as hosts for in vivo study of human tumors and as models for investigation of immune function.

Nude mouse – The nude mouse (Foxn1nu/nu) was first noted as a spontaneous mutant in 1962, initially recognized for being hairless and having a short lifespan [38,39]. Subsequent work revealed absence of the thymus, impaired T cell development, and ability to tolerate xenografts (tissues from other species) [40,41]. Nude mice have great historical importance, but contemporary humanized mice used to engraft human hematopoietic and immune cells are based on different mouse mutants.

Elements of immunodeficiency – Humanized mice must have the following three principal elements of immunodeficiency to allow robust human immune and hematopoietic cell engraftment:

Disruption in the recombinational machinery necessary for immune cell differentiation, satisfied by loss of function of PRKDC, RAG1, or RAG2.

Loss of function mutations of PRKDC, encoding the catalytic subunit of DNA-dependent protein kinase, result in defective repair of double-stranded DNA breaks, resistance to ionizing radiation, and VDJ rearrangement in B and T cells [42]. Prior work established the severe combined immunodeficiency (SCID, PRKDCscid/scid) phenotype and demonstrated that SCID mice can serve as experimental hosts for engrafting human immune cells [43-46]. This property led to SCID mice rapidly becoming a widely used platform in hematological malignancy, infectious disease, and autoimmunity research, even before the molecular pathogenesis of the SCID mutation was understood. Two additional genes, encoding recombination activating genes 1 and 2 (RAG1 and RAG2), also are needed for VDJ rearrangement, and mice deficient in them show profound impairment of B and T cell maturation, and consequently, immunity [47-50].

Disruption of the shared gamma subunit (encoded by IL2RG) of multiple interleukin receptors. This disruption causes X-linked severe combined immune deficiency (X-SCID) in humans and a similar phenotype in mice [51-54]. (See "X-linked severe combined immunodeficiency (X-SCID)".)

Loss of function mutations of IL2RG interfere with high-affinity binding of multiple cytokines including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21.

Carriage of a "human-like" allele of SIRPA, encoding signal regulatory protein alpha type 1 [55,56].

This protein is expressed on macrophages and mediates an inhibitory signal that prevents phagocytosis [57]. Non-obese diabetic (NOD) mice coincidentally harbor a polymorphism in SIRPA that resembles the human protein and thereby protects human cells. For this reason, many humanized mice feature a NOD genetic background, although a few strains have a Balb/c background, which also harbors a more favorable SIRPA allele [58]. A few strains have a C57BL/6 background together with SIRPA or CD47 alleles that allow human cell engraftment.

More than 20 mouse strains and stocks capable of being humanized are available from the major commercial laboratory mouse vendors; descriptions can be found on their websites. Additional strains have been developed by individual laboratories.

Delivery of human cells – To generate humanized mice, an immunodeficient mouse must receive human donor cells. These can be delivered in several ways. Human peripheral blood mononuclear cells or human hematopoietic stem cells can be infused into host mice, which are typically irradiated prior to infusion [44,46]. Alternatively, fetal liver and thymus tissue can be placed under the renal capsule [45].

Engraftment – All of the existing mouse host strains and engraftment strategies display important limitations, and careful planning is necessary to choose the best system to study the relevant biology. Some common problems include development of graft-versus-host disease (GVHD), poor development of lymph nodes, poor maturation of lymphocytes, and limited survival of engrafted tissue. The many available recipient strains represent efforts by numerous investigators to overcome the biological constraints in the context of specific problems encountered in their research.

LIMITATIONS AND CAVEATS — Limitations and caveats with genetically engineered mice include:

Unclear or mixed genetic background – Characteristics of different mouse strains are highly variable, so knowing the background in which a genetic construct has been studied is essential to interpreting its biology. For technical reasons, many genetically engineered mice have been generated on one of the 129 strains, which have been found to be more diverse than previously believed [59-61]. Investigators routinely breed founder animals to a recipient strain, most often C57BL/6. Consequently, the constructs are often studied on a poorly defined "mixed 129 X C57BL/6 background," without further information regarding the relative contributions of the progenitor genomes, number of generations of subsequent inbreeding, or often even the correct strain information regarding the progenitors. While unfortunate, this is the status of most of the extant literature. Efforts to improve reporting of strain background in the future are underway [62].

Risk of insertional mutagenesis – For mice in which the construct has not been targeted to a specific locus, incorporation of the transgene may result in insertional mutagenesis, with the resulting phenotype arising not from the transgene, but from disruption of the gene into which the transgene was placed [63]. The transgene's expression may also be variable according to the properties of the insertion site [64].

Variation in expression levels – A third complication is that multiple copies of the transgene may be inserted into the genome, with consequent differences in transgene expression level. These limitations can be addressed by targeting transgenes to specific sites. One site that allows insertion of a single copy of the transgene while allowing transcription to be mediated by sequences included in the targeting vector is the HPRT locus, encoding the salvage purine utilization enzyme hypoxanthine/guanine phosphoribosyl transferase [65,66].

Challenges in defining causality – The major limitation of knockouts is that the allele generated is, by design, null. Therefore, while they are useful for establishing the role of the target gene in a pathway, it is not necessarily the case that mutations in the target gene account for human diseases or population variation in downstream phenotypes mediated by it. Knock-in strategies can address this by allowing study of a series of mutant alleles. By virtue of being targeted to the homologous locus, the issue of unintentional insertional mutation does not arise with knockout mice.

The limitations related to strain background are significant, particularly because 129-related strains have been the source of many ES cell lines. More recent success in generating successful ES cells from other strains promises to mitigate this problem in the future [67,68].

Off-target effects and Cre toxicity – Another difficulty is that Cre constructs are neither perfectly efficient nor perfectly specific. Thus, "tissue-specific" Cre constructs are sometimes active outside the target tissue, and Cre constructs presumed to be inducible are active in the absence of the inducing substance [69,70]. Furthermore, Cre constructs can exert inherent biological effects, including "Cre toxicity" and Cre-mediated suppression of tumor growth [71-75].

The practical response to these limitations is that when transgenic mice are generated, investigators routinely study animals derived from several different founders. The minimal characterization will generally include estimation of copy number, transgene mRNA level, and transgene protein level. More detailed analysis is then conducted on one or a small number of the transgenic lines. Appropriate and complete control groups need to be characterized in parallel. Careful investigators will also report the breeding history between founder and the analyzed animals.

SUMMARY

Genetic manipulations – The ability to introduce foreign DNA into pluripotent embryonic stem cells is at the core of most genetically engineered mice. Genome editing has greatly reduced the time and expense of creating transgenic animals. (See 'Technical underpinnings and genome editing' above.)

Types of genetically engineered mice

Transgenic mice are those into which foreign DNA has been incorporated into the genome. (See 'Transgenic mice' above.)

Knockout mice depend upon successful gene transfer targeted to disrupt a specific gene to study the consequences of loss of function of the targeted gene directly in vivo. (See 'Knockout mice' above.)

Knock-in technology allows examination of the effects of different mutations on the same gene. (See 'Knock-in mice' above.)

Cre constructs driven by tissue-specific or lineage-specific promoters can restrict transgene disruption or expression to a defined cell population. (See 'Conditional systems' above.)

A variety of reporter constructs have permitted widespread adoption of lineage tracing strategies. (See 'Reporter mice' above.)

Immunodeficient mice can be reconstituted with human constructs to permit better modeling of disease-related research questions. (See 'Humanized immunodeficient mice' above.)

Limitations and caveats – Investigators must consider potential issues related to the genetic background of the animals, risk of insertional mutagenesis, variable expression levels, challenges in defining causality based on gene knockout studies, and off-target effects and Cre toxicity. (See 'Limitations and caveats' above.)

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References

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