Thus, rESC technology has not been developed to its full potential. ![]() With the advent of gene editing in 1-cell embryos, especially clustered regularly interspaced short palindromic repeats (CRISPR-Cas9)-based editing, genetic manipulation in rats has become easier, and many labs have adopted this approach ( Menoret et al., 2010 Vaira et al., 2012). However, rESCs have only rarely been used for gene targeting ( Meek et al., 2010 Men et al., 2012 Tong et al., 2010). The first genuine rESCs were reported in 2008 these cells possess the same properties as mESCs ( Buehr et al., 2008 Li et al., 2008). Many attempts to apply mESC derivation techniques to the derivation of rESCs have failed (e.g., Brenin et al., 1997 Li et al., 2009). As genetic engineering began to drive mammalian research, rats fell behind due to a lack of rat ESCs (rESCs). Prior to the discovery of mESCs, rats were the model of choice for certain fields of research ( Amos-Landgraf et al., 2007 Jacob, 2010 Morrison et al., 2008). Rats have been used for laboratory studies for over 150 years ( Baker et al., 1979 Jacob, 2010). Since then, mice have become the predominant animal system for modeling disease using genetic engineering. Mouse ESCs (mESCs) were first isolated decades ago ( Evans and Kaufman, 1981 Martin, 1981) soon after, modified mESCs were used to produce mice carrying targeted mutations ( Doetschman et al., 1987 Robertson et al., 1986 Thomas and Capecchi, 1987 Zijlstra et al., 1989). Until recently, ESC-based genetic engineering was done exclusively in mice, the only organism for which ESCs were available. High-quality ESCs can be sequentially engineered to produce cells with multiple mutations or with large modifications that span several million base pairs ( Murphy et al., 2014). ESCs are pluripotent self-renewing cells that, when transplanted into preimplantation embryos, contribute to the development of every cell type in the animal, including germ cells, which allows the propagation of genetic modifications to future generations. Historically, the most powerful technology for genetic engineering in mice has been embryonic stem cells (ESCs) ( Bronson and Smithies, 1994 Capecchi, 1989 Smith, 2001). NTRK2 is therefore a potential therapeutic target for activation by agonist antibodies. Binding of brain-derived neurotrophic factor (BDNF) to NTRK2 triggers its dimerization, autophosphorylation, and activation of neuroprotective signaling pathways ( Bai et al., 2010). NTRK2 is a widely distributed neurotrophic receptor in the brain and is highly expressed in the retina ( Chao, 2003). ![]() One example is neurotrophic receptor kinase 2 (NTRK2), a promising target for neuroprotection in degenerative eye diseases such as glaucoma. Gene humanization-the replacement of an endogenous gene with its human counterpart-enables the testing of human monoclonal antibodies in mice for functional activity in a preclinical system, which accelerates the development of new therapies ( Gusarova et al., 2015 Macdonald et al., 2014 Murphy et al., 2014 Stein et al., 2012 Waite et al., 2020). CRE-loxP and Tet-inducible systems enable conditional inactivation or regulation of endogenous genes or transgenes with a wide range of functions ( Aiba and Nakao, 2007 Jaisser, 2000 Lau et al., 2011). ![]() Complex modifications can be combined to expand the power of these models, as in immunodeficient models to study hematopoiesis and tumor biology ( Mashimo et al., 2012 Rongvaux et al., 2013 Strowig et al., 2011). Genetic engineering enables the production of disease-associated genotypes in model animal systems, especially mice ( White et al., 1995 Yue et al., 2006).
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