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Adult Stem Cell Plasticity
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
The first two attempts to demonstrate BM-derived neurons were published in the journal Science in December of 2000. Brazelton and colleagues59 used a GFP transgenic mouse strain as a donor to recipients lacking the transgene. Analysis focused on the olfactory bulb, but GFP+ (donor) cells were also found in the hippocampus, cortex, and cerebellum. Using laser scanning confocal microscopy to visualize very thin (~0.3μm) sections of the brain, GFP+ cells that coexpressed neuron specific antigens (NeuN, neurofilament NF-H, and class III β-tubulin) comprised 0.2-0.3% of all olfactory bulb neurons after BM transplantation. The highest frequency of BM-derived neurons was in the superficial axonal layer of the olfactory bulb, a region known to exhibit high rates of neurogenesis.60,61 The majority of the GFP+ neuron-like cells also had a triangular shape, indicative of neurons, and a few also possessed long cellular extensions, which could represent axonal outgrowths. The phosphorylation state of cyclic AMP response element-binding (CREB) transcription factor in the putative GFP+ neurons was similar to that in surrounding neurons, suggesting a functional similarity in how these cells and neighboring neurons interact with the extracellular environment.62 In contrast to other reports, no BM-derived astrocytes were detected in this study.
Dysmorphology and genetic syndromes
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
These exciting developments offer the possibility of matching human developmental defects with the individual genetic steps in embryonic development. The possibility of constructing transgenic mouse models in addition to those occurring naturally further strengthens this approach. Malformation syndromes can now be seen as the equivalent of inborn errors of metabolism, specific defects that will eventually tell us as much about normal embryonic development as rare inborn errors have told us about metabolic pathways. Epstein's Inborn Errors of Development (see Appendix 1) gives an authoritative source for defects in different developmental pathways, although numerous changes have accumulated since then.
Animal Models of Down Syndrome and Other Genetic Diseases Associated with Mental Retardation
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Angela J. Villar, Charles J. Epstein
There are some serious limitations inherent in the approaches directed at dissecting individual gene function. The random site of integration and the variability of copy number can affect the quantitative expression of the transgene. Other concerns are the possible disruption of an endogenous gene by a transgenic insertion event, which can result in a mutant phenotype as a consequence of a disruption, deletion, or translocation, rather than as a consequenceof transgenesis. Finally, whereas genes under control of their natural promoters are expected to recapitulate the cell-type- and stage-specific expression of the endogenous genes, reflecting the genetic situation in DS, the use of heterologous promoters that may allow the generation of inducible transgenic models can lead to nonphysiological effects. Therefore, the best way to produce a transgenic mouse is to introduce the gene under the transcriptional control of its own promoter. In addition, when selecting a candidate gene for the making of a transgenic mouse, knowledge of the functions of the protein that the transgene encodes and of its spatiotemporal pattern of expression should be considered.
Renal ciliopathies: promising drug targets and prospects for clinical trials
Published in Expert Opinion on Therapeutic Targets, 2023
Laura Devlin, Praveen Dhondurao Sudhindar, John A. Sayer
Rodents have been invaluable in ciliopathy research, especially as they can be utilized to study post-embryonic phenotypes including adult histology and fibrosis [23]. Prior to the discovery of genetic causes of renal ciliopathies rodent strains which develop spontaneous renal cysts were utilized as disease models; an example is cpk mice as a murine model of ARPKD [38,127–129]. With improvement in gene sequencing and development of genetic modification techniques numerous transgenic animals with gene knockouts, knockins, and patient-specific point mutations have been designed. The use of inbred transgenic mouse models also helps to remove confounding influences such as oligogenecity and triallelism, to understand the exact pathogenic mechanisms driven by specific genetic mutations [127]. Biological parameters such as kidney volume, kidney weight, and urine/plasma biomarkers [130] can be measured, histopathology examined, and molecular pathways investigated by transcriptomics and proteomics, to uncover disease mechanisms and determine the efficacy of potential therapeutics.
What is the gold standard model for Alzheimer’s disease drug discovery and development?
Published in Expert Opinion on Drug Discovery, 2021
Ramón Cacabelos, Iván Carrera, Olaia Martínez-Iglesias, Natalia Cacabelos, Vinogran Naidoo
Transgenic mice are the most frequently used experimental models in AD research. Over 90% of studies with transgenic models are performed in genetically manipulated mice [9,16] (Tables 1–3) and about 60% of all basic studies on AD use rodents (Figure 1). Transgenic mouse models (TMMs) are generated by transfer of human genes into the murine genome. TMMs can be monogenic, bigenic, trigenic, tetragenic, pentagenic, hexagenic or polygenic, depending upon the number of AD genes incorporated into the model. TMMs can also be monolocative (focused on a single genetic variant) or multilocative (involving several mutations in the same gene). The C57Bl/6 mouse strain is the most common wild-type background in TMMs [16]. There are approximately 260 different TMMs expressing one to six different genes. The genes which are the substrates of the TMMs developed thus far are the following (in decreasing order): APP variants are present in 30,8% of the reported models (wild-type APP695 shares 97% sequence homology with human APP), PSEN1 in 16,5%, MAPT and TREM2 in 12,7%, APOE in 10,8%, PSEN2 and BACE1 in 2,7%, BRI2/ITM2B and PLCG2 in 1,2%, ABCA7 and AGER in 0.8%, and APLP2, PDGFRB, NOS2, BIN1, COPS5, ATG161I, CEACAM1, CLASP2, CR1, CR2, IL1, KIF2IB, MTHFR, RAB5A, AMP8, SNX1, SORL1 and MMU1716 in 0.4% of the reported models (Table 2).
HLA transgenic mice: application in reproducing idiosyncratic drug toxicity
Published in Drug Metabolism Reviews, 2020
Takeshi Susukida, Shigeki Aoki, Tomohiro Shirayanagi, Yushiro Yamada, Saki Kuwahara, Kousei Ito
To address this need, HLA transgenic mouse lines carrying either human-mouse chimeric HLA-B*57:01 or HLA-B*57:03 (negative control) were generated by our group to evaluate abacavir-induced hypersensitivity (Song et al. 2018; Susukida et al. 2018). Using this mouse model, immune-mediated skin toxicity was successfully demonstrated with abacavir in HLA-B*57:01 transgenic mouse, but not in HLA-B*57:03 transgenic mouse. Moreover, abacavir-induced liver injury was observed when mice were treated with CpG-oligodeoxynucleotides (ODN), a TLR9 agonist. A similar transgenic mouse model was recently developed in another laboratory, with minor genetic differences from our model (Cardone et al. 2018). Similar to our mouse line, the authors were able to achieve abacavir-induced skin toxicity in their human-mouse chimeric HLA-B*57:01 transgenic mice after depletion of CD4+ T cells. In addition, the HLA-B*57:01 mouse line also allows for the evaluation of flucloxacillin (FLUX)-induced liver injury, an area that is currently under investigation in our group.