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Transgenic Mice in Human Diseases: Insights from Molecular Research 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 30983

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Special Issue Editor

Dr. Timofey S. Rozhdestvensky

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Guest Editor

Medical Faculty, Core Facility Transgenic Animal and Genetic Engineering Models (TRAM), University of Muenster, Von-Esmarch-Str. 56, D-48149 Muenster, Germany
Interests: genome editing; CRISPR-Cas9 technology; programmable DNA endonucleases; nervous system diseases; RNA biology; disease-associated RNAs; non-protein coding RNAs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Transgenic mouse models are essential for understanding the molecular mechanisms and pathogenicity of the majority of human diseases. Research based on live mouse models is important to discover and/or improve methods for the prevention, diagnosis, and treatment of diseases.

This Special Issue aims to cover all areas of molecular-based research to study various human diseases using genetically engineered mouse models. It welcomes original research, reviews, and short communication articles on cellular and molecular analyses of transgenic mouse models that includes, but is not limited to, functional genomics of disease, epigenomics, proteomics, RNA biology, systems biology, approaches and methods of mouse genome editing, software tools, etc.

Generation of transgenic mouse models and targeting constructs;

Mouse genome editing approaches;

Transgenic mouse models in cancer research;

Transgenic mouse models to study infection diseases;

Transgenic mouse models for mitochondrial diseases;

Transgenic mouse models in:

Cardiovascular diseases;

Developmental disorders;

Digestive system diseases;

Endocrine system diseases;

Immune diseases;

Integumentary system diseases;

Lymphatic system diseases;

Metabolism, obesity, and metabolic diseases;

Nervous system diseases (including sensory organs disorders);

Reproductive system diseases;

Respiratory system diseases;

Skeletal and muscular systems diseases;

Urinary system diseases;

etc.

Dr. Timofey S. Rozhdestvensky
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (9 papers)

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Research

Jump to: Review

15 pages, 1092 KiB

Open AccessArticle

Dysregulated Brain Protein Phosphorylation Linked to Increased Human Tau Expression in the hTau Transgenic Mouse Model

by Isidro Ferrer, Pol Andrés-Benito, Karina Ausín, Paz Cartas-Cejudo, Mercedes Lachén-Montes, José Antonio del Rio, Joaquín Fernández-Irigoyen and Enrique Santamaría

Int. J. Mol. Sci. 2022, 23(12), 6427; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23126427 - 08 Jun 2022

Viewed by 1858

Abstract

Altered protein phosphorylation is a major pathologic modification in tauopathies and Alzheimer’s disease (AD) linked to abnormal tau fibrillar deposits in neurofibrillary tangles (NFTs) and pre-tangles and β-amyloid deposits in AD. hTau transgenic mice, which express 3R and less 4R human tau with no mutations in a murine knock-out background, show increased tau deposition in neurons but not NFTs and pre-tangles at the age of nine months. Label-free (phospho)proteomics and SWATH-MS identified 2065 proteins in hTau and wild-type (WT) mice. Only six proteins showed increased levels in hTau; no proteins were down-regulated. Increased tau phosphorylation in hTau was detected at Ser199, Ser202, Ser214, Ser396, Ser400, Thr403, Ser404, Ser413, Ser416, Ser422, Ser491, and Ser494, in addition to Thr181, Thr231, Ser396/Ser404, but not at Ser202/Thr205. In addition, 4578 phosphopeptides (corresponding to 1622 phosphoproteins) were identified in hTau and WT mice; 64 proteins were differentially phosphorylated in hTau. Sixty proteins were grouped into components of membranes, membrane signaling, synapses, vesicles, cytoskeleton, DNA/RNA/protein metabolism, ubiquitin/proteasome system, cholesterol and lipid metabolism, and cell signaling. These results showed that over-expression of human tau without pre-tangle and NFT formation preferentially triggers an imbalance in the phosphorylation profile of specific proteins involved in the cytoskeletal–membrane-signaling axis. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 2.0)

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19 pages, 2832 KiB

Open AccessArticle

Mitochondrial rRNA Methylation by Mettl15 Contributes to the Exercise and Learning Capability in Mice

by Olga A. Averina, Ivan G. Laptev, Mariia A. Emelianova, Oleg A. Permyakov, Sofia S. Mariasina, Alyona I. Nikiforova, Vasily N. Manskikh, Olga O. Grigorieva, Anastasia K. Bolikhova, Gennady A. Kalabin, Olga A. Dontsova and Petr V. Sergiev

Int. J. Mol. Sci. 2022, 23(11), 6056; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23116056 - 27 May 2022

Cited by 3 | Viewed by 2478

Abstract

Mitochondrial translation is a unique relic of the symbiotic origin of the organelle. Alterations of its components cause a number of severe human diseases. Hereby we report a study of mice devoid of Mettl15 mitochondrial 12S rRNA methyltransferase, responsible for the formation of m⁴C839 residue (human numbering). Homozygous Mettl15^−/− mice appeared to be viable in contrast to other mitochondrial rRNA methyltransferase knockouts reported earlier. The phenotype of Mettl15^−/− mice is much milder than that of other mutants of mitochondrial translation apparatus. In agreement with the results obtained earlier for cell cultures with an inactivated Mettl15 gene, we observed accumulation of the RbfA factor, normally associated with the precursor of the 28S subunit, in the 55S mitochondrial ribosome fraction of knockout mice. A lack of Mettl15 leads to a lower blood glucose level after physical exercise relative to that of the wild-type mice. Mettl15^−/− mice demonstrated suboptimal muscle performance and lower levels of Cox3 protein synthesized by mitoribosomes in the oxidative soleus muscles. Additionally, we detected decreased learning capabilities in the Mettl15^−/− knockout mice in the tests with both positive and negative reinforcement. Such properties make Mettl15^−/− knockout mice a suitable model for mild mitochondriopathies. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 2.0)

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16 pages, 2325 KiB

Open AccessArticle

Impact of Cerebral Amyloid Angiopathy in Two Transgenic Mouse Models of Cerebral β-Amyloidosis: A Neuropathological Study

by Paula Marazuela, Berta Paez-Montserrat, Anna Bonaterra-Pastra, Montse Solé and Mar Hernández-Guillamon

Int. J. Mol. Sci. 2022, 23(9), 4972; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094972 - 29 Apr 2022

Cited by 10 | Viewed by 2559

Abstract

The pathological accumulation of parenchymal and vascular amyloid-beta (Aβ) are the main hallmarks of Alzheimer’s disease (AD) and Cerebral Amyloid Angiopathy (CAA), respectively. Emerging evidence raises an important contribution of vascular dysfunction in AD pathology that could partially explain the failure of anti-Aβ therapies in this field. Transgenic mice models of cerebral β-amyloidosis are essential to a better understanding of the mechanisms underlying amyloid accumulation in the cerebrovasculature and its interactions with neuritic plaque deposition. Here, our main objective was to evaluate the progression of both parenchymal and vascular deposition in APP23 and 5xFAD transgenic mice in relation to age and sex. We first showed a significant age-dependent accumulation of extracellular Aβ deposits in both transgenic models, with a greater increase in APP23 females. We confirmed that CAA pathology was more prominent in the APP23 mice, demonstrating a higher progression of Aβ-positive vessels with age, but not linked to sex, and detecting a pronounced burden of cerebral microbleeds (cMBs) by magnetic resonance imaging (MRI). In contrast, 5xFAD mice did not present CAA, as shown by the negligible Aβ presence in cerebral vessels and the occurrence of occasional cMBs comparable to WT mice. In conclusion, the APP23 mouse model is an interesting tool to study the overlap between vascular and parenchymal Aβ deposition and to evaluate future disease-modifying therapy before its translation to the clinic. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 2.0)

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15 pages, 1904 KiB

Open AccessArticle

TRAPing Ghrelin-Activated Circuits: A Novel Tool to Identify, Target and Control Hormone-Responsive Populations in TRAP2 Mice

by Iris Stoltenborg, Fiona Peris-Sampedro, Erik Schéle, Marie V. Le May, Roger A. H. Adan and Suzanne L. Dickson

Int. J. Mol. Sci. 2022, 23(1), 559; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010559 - 05 Jan 2022

Cited by 2 | Viewed by 4978

Abstract

The availability of Cre-based mouse lines for visualizing and targeting populations of hormone-sensitive cells has helped identify the neural circuitry driving hormone effects. However, these mice have limitations and may not even be available. For instance, the development of the first ghrelin receptor (Ghsr)-IRES-Cre model paved the way for using the Cre-lox system to identify and selectively manipulate ghrelin-responsive populations. The insertion of the IRES-Cre cassette, however, interfered with Ghsr expression, resulting in defective GHSR signaling and a pronounced phenotype in the homozygotes. As an alternative strategy to target ghrelin-responsive cells, we hereby utilize TRAP2 (targeted recombination in active populations) mice in which it is possible to gain genetic access to ghrelin-activated populations. In TRAP2 mice crossed with a reporter strain, we visualized ghrelin-activated cells and found, as expected, much activation in the arcuate nucleus (Arc). We then stimulated this population using a chemogenetic approach and found that this was sufficient to induce an orexigenic response of similar magnitude to that induced by peripheral ghrelin injection. The stimulation of this population also impacted food choice. Thus, the TRAPing of hormone-activated neurons (here exemplified by ghrelin-activated pathways) provides a complimentary/alternative technique to visualize, access and control discrete pathways, linking hormone action to circuit function. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 2.0)

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13 pages, 3572 KiB

Open AccessArticle

The Receptor AT1 Appears to Be Important for the Maintenance of Bone Mass and AT2 Receptor Function in Periodontal Bone Loss Appears to Be Regulated by AT1 Receptor

by Maria Laura de Souza Lima, Agnes Andrade Martins, Caroline Addison Carvalho Xavier de Medeiros, Gerlane Coelho Bernardo Guerra, Robson Santos, Michael Bader, Flavia Q. Pirih, Raimundo Fernandes de Araújo Júnior, Gerly Anne de Castro Brito, Renata Ferreira de Carvalho Leitão, Rafaela Alcindo Silva, Stphannie Jamyla de Araújo Barbosa, Rômulo Camilo de Oliveira Melo and Aurigena Antunes de Araújo

Int. J. Mol. Sci. 2021, 22(23), 12849; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312849 - 27 Nov 2021

Cited by 2 | Viewed by 1870

Abstract

A large number of experimental studies has demonstrated that angiotensin II (Ang II) is involved in key events of the inflammatory process. This study aimed to evaluate the role of Ang II type 1 (AT1) and Ang II type 2 (AT2) receptors on periodontitis. Methods: Experimental periodontitis was induced by placing a 5.0 nylon thread ligature around the second upper left molar of AT1 mice, no-ligature or ligature (AT1-NL and AT1-L), AT2 (AT2-NL or AT2-L) and wild type (WT-NL or L). Alveolar bone loss was scanned using Micro-CT. Cytokines, peptides and enzymes were analyzed from gingival tissues by Elisa and RT-PCR. Results: The blockade of AT1 receptor resulted in bone loss, even in healthy animals. Ang II receptor blockades did not prevent linear bone loss. Ang II and Ang 1-7 levels were significantly increased in the AT2-L (p < 0.01) group compared to AT2-NL and AT1-L. The genic expression of the Mas receptor was significantly increased in WT-L and AT2-L compared to (WT-NL and AT2-NL, respectively) and in AT1-L. Conclusions: Our data suggest that the receptor AT1 appears to be important for the maintenance of bone mass. AT2 receptor molecular function in periodontitis appears to be regulated by AT1. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 2.0)

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25 pages, 5046 KiB

Open AccessArticle

Identification of Impacted Pathways and Transcriptomic Markers as Potential Mediators of Pulmonary Fibrosis in Transgenic Mice Expressing Human IGFBP5

by Xinh-Xinh Nguyen, Ludivine Renaud and Carol Feghali-Bostwick

Int. J. Mol. Sci. 2021, 22(22), 12609; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212609 - 22 Nov 2021

Cited by 4 | Viewed by 2983

Abstract

Pulmonary fibrosis is a serious disease characterized by extracellular matrix (ECM) component overproduction and remodeling. Insulin-like growth factor-binding protein 5 (IGFBP5) is a conserved member of the IGFBP family of proteins that is overexpressed in fibrotic tissues and promotes fibrosis. We used RNA sequencing (RNAseq) to identify differentially expressed genes (DEGs) between primary lung fibroblasts (pFBs) of homozygous (HOMO) transgenic mice expressing human IGFBP5 (hIGFBP5) and wild type mice (WT). The results of the differential expression analysis showed 2819 DEGs in hIGFBP5 pFBs. Functional enrichment analysis confirmed the pro-fibrotic character of IGFBP5 and revealed its impact on fundamental signaling pathways, including cytokine–cytokine receptor interaction, focal adhesion, AGE-RAGE signaling, calcium signaling, and neuroactive ligand-receptor interactions, to name a few. Noticeably, 7% of the DEGs in hIGFBP5-expressing pFBs are receptors and integrins. Furthermore, hub gene analysis revealed 12 hub genes including Fpr1, Bdkrb2, Mchr1, Nmur1, Cnr2, P2ry14, and Ptger3. Validation assays were performed to complement the RNAseq data. They confirmed significant differences in the levels of the corresponding proteins in cultured pFBs. Our study provides new insights into the molecular mechanism(s) of IGFBP5-associated pulmonary fibrosis through possible receptor interactions that drive fibrosis and tissue remodeling. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 2.0)

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14 pages, 2676 KiB

Open AccessArticle

Pannexin 1 Transgenic Mice: Human Diseases and Sleep-Wake Function Revision

by Nariman Battulin, Vladimir M. Kovalzon, Alexey Korablev, Irina Serova, Oxana O. Kiryukhina, Marta G. Pechkova, Kirill A. Bogotskoy, Olga S. Tarasova and Yuri Panchin

Int. J. Mol. Sci. 2021, 22(10), 5269; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105269 - 17 May 2021

Cited by 2 | Viewed by 2327

Abstract

In humans and other vertebrates pannexin protein family was discovered by homology to invertebrate gap junction proteins. Several biological functions were attributed to three vertebrate pannexins members. Six clinically significant independent variants of the PANX1 gene lead to human infertility and oocyte development defects, and the Arg217His variant was associated with pronounced symptoms of primary ovarian failure, severe intellectual disability, sensorineural hearing loss, and kyphosis. At the same time, only mild phenotypes were observed in Panx1 knockout mice. In addition, a passenger mutation was identified in a popular line of Panx1 knockout mice, questioning even those effects. Using CRISPR/Cas9, we created a new line of Panx1 knockout mice and a new line of mice with the clinically significant Panx1 substitution (Arg217His). In both cases, we observed no significant changes in mouse size, weight, or fertility. In addition, we attempted to reproduce a previous study on sleep/wake and locomotor activity functions in Panx1 knockout mice and found that previously reported effects were probably not caused by the Panx1 knockout itself. We consider that the pathological role of Arg217His substitution in Panx1, and some Panx1 functions in general calls for a re-evaluation. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 2.0)

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Review

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46 pages, 4173 KiB

Open AccessReview

Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis

by Raquel Sanchez-Varo, Marina Mejias-Ortega, Juan Jose Fernandez-Valenzuela, Cristina Nuñez-Diaz, Laura Caceres-Palomo, Laura Vegas-Gomez, Elisabeth Sanchez-Mejias, Laura Trujillo-Estrada, Juan Antonio Garcia-Leon, Ines Moreno-Gonzalez, Marisa Vizuete, Javier Vitorica, David Baglietto-Vargas and Antonia Gutierrez

Int. J. Mol. Sci. 2022, 23(10), 5404; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105404 - 12 May 2022

Cited by 33 | Viewed by 8298

Abstract

Alzheimer’s disease (AD) constitutes the most prominent form of dementia among elderly individuals worldwide. Disease modeling using murine transgenic mice was first initiated thanks to the discovery of heritable mutations in amyloid precursor protein (APP) and presenilins (PS) genes. However, due to the repeated failure of translational applications from animal models to human patients, along with the recent advances in genetic susceptibility and our current understanding on disease biology, these models have evolved over time in an attempt to better reproduce the complexity of this devastating disease and improve their applicability. In this review, we provide a comprehensive overview about the major pathological elements of human AD (plaques, tauopathy, synaptic damage, neuronal death, neuroinflammation and glial dysfunction), discussing the knowledge that available mouse models have provided about the mechanisms underlying human disease. Moreover, we highlight the pros and cons of current models, and the revolution offered by the concomitant use of transgenic mice and omics technologies that may lead to a more rapid improvement of the present modeling battery. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 2.0)

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14 pages, 930 KiB

Open AccessReview

Mouse Models of CMML

by Ekaterina Belotserkovskaya and Oleg Demidov

Int. J. Mol. Sci. 2021, 22(21), 11510; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111510 - 26 Oct 2021

Cited by 2 | Viewed by 2310

Abstract

Chronic myelomonocytic leukemia (CMML) is a rare and challenging type of myeloproliferative neoplasm. Poor prognosis and high mortality, associated predominantly with progression to secondary acute myeloid leukemia (sAML), is still an unsolved problem. Despite a growing body of knowledge about the molecular repertoire of this disease, at present, the prognostic significance of CMML-associated mutations is controversial. The absence of available CMML cell lines and the small number of patients with CMML make pre-clinical testing and clinical trials complicated. Currently, specific therapy for CMML has not been approved; most of the currently available therapeutic approaches are based on myelodysplastic syndrome (MDS) and other myeloproliferative neoplasm (MNP) studies. In this regard, the development of the robust CMML animal models is currently the focus of interest. This review describes important studies concerning animal models of CMML, examples of methodological approaches, and the obtained hematologic phenotypes. Full article

(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 2.0)

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