Genetically modified mouse models are now indispensable and highly versatile tools used in practically every branch of research. First genetically modified mouse was created in 1974 by Beatrice Mintz and Rudolf Jaenish[1] by introduction of a transgene into early stage embryo using a viral vector. This undoubtedly was a milestone but using this approach, mice did not transmit the transgene to their offspring thus limiting impact. Major step forward in this area was possible after identification of embryonic stem cells[2], which when genetically modified could then be used to create complete transgenic organism including germline transmission[3]. Impact of this discovery was recognized by 2007 Nobel Prize in Medicine and Physiology. Currently, generation of transgenic mouse model is a routine research technique with a price tag below $5,000 and a time line for production of new transgenic animal counted in weeks. Transgenic models are particularly important for studies on neuropathologies and developing new treatments. One spectacular example application is with genetically encoded calcium indicator (GCaMP) mice allowing visualization of neuronal function in living animals using two-photon microscopy[4]. Generation of knockout mice allows shutting down function of selected genes such as recombination activating gene 2 (Rag2). Rag2 knockout mice are characterized by severe immunodeficiency and as such are an excellent recipients of allografts or even xenografts without the risk of mounting immune response or rejection, exploited heavily in regenerative medicine and oncology[5]. Multiple transgenics can be developed by cross-breeding of two or more lines of mice, each with unique features. One example of such combined transgenics is hypomyelinated shiverer mice with deletion mutation in MBP gene and Rag2 model. Resulting hydride can be used as a recipient of human stem cell xenografts for studies on myelination[6]. Transgenic reporter mouse models have also been developed specifically for studies using MRI such as ferritin reporter[7]. Progress in genetic engineering continues and latest addition to the methodological arsenal tools for genome editing is highly specific and precise genome editing using CRISPR technology. This enables efficient development of new transgenic models[8] or ad hoc local creation of genetic modifications in tissues[9]

Acknowledgements

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References

1. Jaenisch, R. and B. Mintz, Simian virus 40 DNA sequences in DNA of healthy adult mice derived from preimplantation blastocysts injected with viral DNA. Proc Natl Acad Sci U S A, 1974. 71(4): p. 1250-4. 2. Evans, M.J. and M.H. Kaufman, Establishment in culture of pluripotential cells from mouse embryos. Nature, 1981. 292(5819): p. 154-6. 3. Gordon, J.W. and F.H. Ruddle, Integration and stable germ line transmission of genes injected into mouse pronuclei. Science, 1981. 214(4526): p. 1244-6. 4. Meng, G., et al., High-throughput synapse-resolving two-photon fluorescence microendoscopy for deep-brain volumetric imaging in vivo. Elife, 2019. 8. 5. Goldman, J.P., et al., Enhanced human cell engraftment in mice deficient in RAG2 and the common cytokine receptor gamma chain. Br J Haematol, 1998. 103(2): p. 335-42. 6. Lyczek, A., et al., Transplanted human glial-restricted progenitors can rescue the survival of dysmyelinated mice independent of the production of mature, compact myelin. Exp Neurol, 2017. 291: p. 74-86. 7. Cohen, B., et al., Ferritin as an endogenous MRI reporter for noninvasive imaging of gene expression in C6 glioma tumors. Neoplasia, 2005. 7(2): p. 109-17. 8. Modzelewski, A.J., et al., Efficient mouse genome engineering by CRISPR-EZ technology. Nat Protoc, 2018. 13(6): p. 1253-1274. 9. Moreno, A.M., et al., In Situ Gene Therapy via AAV-CRISPR-Cas9-Mediated Targeted Gene Regulation. Mol Ther, 2018. 26(7): p. 1818-1827.