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11 pages, 3123 KiB

Open AccessArticle

Phenotypic Effects of Homeodomain-Interacting Protein Kinase 2 Deletion in Mice

by Davide De Biase, Valeria Valente, Andrea Conte, Francesca Cammarota, Nicola Boccella, Lucia D’Esposito, Ilaria d’Aquino, Orlando Paciello, Simona Paladino and Giovanna Maria Pierantoni

Int. J. Mol. Sci. 2021, 22(15), 8294; https://doi.org/10.3390/ijms22158294 - 2 Aug 2021

Cited by 6 | Viewed by 2708

Abstract

Homeodomain-interacting protein kinase 2 (HIPK2) is a serine-threonine kinase that phosphorylates various transcriptional and chromatin regulators, thus modulating numerous important cellular processes, such as proliferation, apoptosis, DNA damage response, and oxidative stress. The role of HIPK2 in the pathogenesis of cancer and fibrosis [...] Read more.

Homeodomain-interacting protein kinase 2 (HIPK2) is a serine-threonine kinase that phosphorylates various transcriptional and chromatin regulators, thus modulating numerous important cellular processes, such as proliferation, apoptosis, DNA damage response, and oxidative stress. The role of HIPK2 in the pathogenesis of cancer and fibrosis is well established, and evidence of its involvement in the homeostasis of multiple organs has been recently emerging. We have previously demonstrated that Hipk2-null (Hipk2-KO) mice present cerebellar alterations associated with psychomotor abnormalities and that the double ablation of HIPK2 and its interactor HMGA1 causes perinatal death due to respiratory failure. To identify other alterations caused by the loss of HIPK2, we performed a systematic morphological analysis of Hipk2-KO mice. Post-mortem examinations and histological analysis revealed that Hipk2 ablation causes neuronal loss, neuronal morphological alterations, and satellitosis throughout the whole central nervous system (CNS); a myopathic phenotype characterized by variable fiber size, mitochondrial proliferation, sarcoplasmic inclusions, morphological alterations at neuromuscular junctions; and a cardiac phenotype characterized by fibrosis and cardiomyocyte hypertrophy. These data demonstrate the importance of HIPK2 in the physiology of skeletal and cardiac muscles and of different parts of the CNS, thus suggesting its potential relevance for different new aspects of human pathology. Full article

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

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13 pages, 2972 KiB

Open AccessArticle

Hops/Tmub1 Heterozygous Mouse Shows Haploinsufficiency Effect in Influencing p53-Mediated Apoptosis

by Simona Ferracchiato, Nicola Di-Iacovo, Damiano Scopetti, Danilo Piobbico, Marilena Castelli, Stefania Pieroni, Marco Gargaro, Giorgia Manni, Stefano Brancorsini, Maria Agnese Della-Fazia and Giuseppe Servillo

Int. J. Mol. Sci. 2021, 22(13), 7186; https://doi.org/10.3390/ijms22137186 - 2 Jul 2021

Cited by 3 | Viewed by 2716

Abstract

HOPS is a ubiquitin-like protein implicated in many aspects of cellular function including the regulation of mitotic activity, proliferation, and cellular stress responses. In this study, we focused on the complex relationship between HOPS and the tumor suppressor p53, investigating both transcriptional and [...] Read more.

HOPS is a ubiquitin-like protein implicated in many aspects of cellular function including the regulation of mitotic activity, proliferation, and cellular stress responses. In this study, we focused on the complex relationship between HOPS and the tumor suppressor p53, investigating both transcriptional and non-transcriptional p53 responses. Here, we demonstrated that Hops heterozygous mice and mouse embryonic fibroblasts exhibit an impaired DNA-damage response to etoposide-induced double-strand breaks when compared to wild-type genes. Specifically, alterations in HOPS levels caused significant defects in the induction of apoptosis, including a reduction in p53 protein level and percentage of apoptotic cells. We also analyzed the effect of reduced HOPS levels on the DNA-damage response by examining the transcript profiles of p53-dependent genes, showing a suggestive deregulation of the mRNA levels for a number of p53-dependent genes. Taken together, these results show an interesting haploinsufficiency effect mediated by Hops monoallelic deletion, which appears to be enough to destabilize the p53 protein and its functions. Finally, these data indicate a novel role for Hops as a tumor-suppressor gene in DNA damage repair in mammalian cells. Full article

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

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18 pages, 8368 KiB

Open AccessArticle

Molecular, Cellular and Functional Changes in the Retinas of Young Adult Mice Lacking the Voltage-Gated K⁺ Channel Subunits Kv8.2 and K2.1

by Xiaotian Jiang, Rabab Rashwan, Valentina Voigt, Jeanne Nerbonne, David M. Hunt and Livia S. Carvalho

Int. J. Mol. Sci. 2021, 22(9), 4877; https://doi.org/10.3390/ijms22094877 - 5 May 2021

Cited by 9 | Viewed by 2841

Abstract

Cone Dystrophy with Supernormal Rod Response (CDSRR) is a rare autosomal recessive disorder leading to severe visual impairment in humans, but little is known about its unique pathophysiology. We have previously shown that CDSRR is caused by mutations in the KCNV2 (Potassium Voltage-Gated [...] Read more.

Cone Dystrophy with Supernormal Rod Response (CDSRR) is a rare autosomal recessive disorder leading to severe visual impairment in humans, but little is known about its unique pathophysiology. We have previously shown that CDSRR is caused by mutations in the KCNV2 (Potassium Voltage-Gated Channel Modifier Subfamily V Member 2) gene encoding the Kv8.2 subunit, a modulatory subunit of voltage-gated potassium (Kv) channels. In a recent study, we validated a novel mouse model of Kv8.2 deficiency at a late stage of the disease and showed that it replicates the human electroretinogram (ERG) phenotype. In this current study, we focused our investigation on young adult retinas to look for early markers of disease and evaluate their effect on retinal morphology, electrophysiology and immune response in both the Kv8.2 knockout (KO) mouse and in the Kv2.1 KO mouse, the obligate partner of Kv8.2 in functional retinal Kv channels. By evaluating the severity of retinal dystrophy in these KO models, we demonstrated that retinas of Kv KO mice have significantly higher apoptotic cells, a thinner outer nuclear cell layer and increased activated microglia cells in the subretinal space. Our results indicate that in the murine retina, the loss of Kv8.2 subunits contributes to early cellular and physiological changes leading to retinal dysfunction. These results could have potential implications in the early management of CDSRR despite its relatively nonprogressive nature in humans. Full article

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

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21 pages, 11372 KiB

Open AccessArticle

Human Somatostatin SST₄ Receptor Transgenic Mice: Construction and Brain Expression Pattern Characterization

by Balázs Nemes, Kata Bölcskei, Angéla Kecskés, Viktória Kormos, Balázs Gaszner, Timea Aczél, Dániel Hegedüs, Erika Pintér, Zsuzsanna Helyes and Zoltán Sándor

Int. J. Mol. Sci. 2021, 22(7), 3758; https://doi.org/10.3390/ijms22073758 - 4 Apr 2021

Cited by 12 | Viewed by 3330

Abstract

Somatostatin receptor subtype 4 (SST₄) has been shown to mediate analgesic, antidepressant and anti-inflammatory functions without endocrine actions; therefore, it is proposed to be a novel target for drug development. To overcome the species differences of SST₄ receptor expression and [...] Read more.

Somatostatin receptor subtype 4 (SST₄) has been shown to mediate analgesic, antidepressant and anti-inflammatory functions without endocrine actions; therefore, it is proposed to be a novel target for drug development. To overcome the species differences of SST₄ receptor expression and function between humans and mice, we generated an SST₄ humanized mouse line to serve as a translational animal model for preclinical research. A transposon vector containing the hSSTR4 and reporter gene construct driven by the hSSTR4 regulatory elements were created. The vector was randomly inserted in Sstr4-deficient mice. hSSTR4 expression was detected by bioluminescent in vivo imaging of the luciferase reporter predominantly in the brain. RT-qPCR confirmed the expression of the human gene in the brain and various peripheral tissues consistent with the in vivo imaging. RNAscope in situ hybridization revealed the presence of hSSTR4 transcripts in glutamatergic excitatory neurons in the CA1 and CA2 regions of the hippocampus; in the GABAergic interneurons in the granular layer of the olfactory bulb and in both types of neurons in the primary somatosensory cortex, piriform cortex, prelimbic cortex and amygdala. This novel SST₄ humanized mouse line might enable us to investigate the differences of human and mouse SST₄ receptor expression and function and assess the effects of SST₄ receptor agonist drug candidates. Full article

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

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16 pages, 10100 KiB

Open AccessArticle

Dimethyl Trisulfide Diminishes Traumatic Neuropathic Pain Acting on TRPA1 Receptors in Mice

by Ágnes Dombi, Csenge Sánta, István Z. Bátai, Viktória Kormos, Angéla Kecskés, Valéria Tékus, Krisztina Pohóczky, Kata Bölcskei, Erika Pintér and Gábor Pozsgai

Int. J. Mol. Sci. 2021, 22(7), 3363; https://doi.org/10.3390/ijms22073363 - 25 Mar 2021

Cited by 14 | Viewed by 2995

Abstract

Pharmacotherapy of neuropathic pain is still challenging. Our earlier work indicated an analgesic effect of dimethyl trisulfide (DMTS), which was mediated by somatostatin released from nociceptor nerve endings acting on SST₄ receptors. Somatostatin release occurred due to TRPA1 ion channel activation. In [...] Read more.

Pharmacotherapy of neuropathic pain is still challenging. Our earlier work indicated an analgesic effect of dimethyl trisulfide (DMTS), which was mediated by somatostatin released from nociceptor nerve endings acting on SST₄ receptors. Somatostatin release occurred due to TRPA1 ion channel activation. In the present study, we investigated the effect of DMTS in neuropathic pain evoked by partial ligation of the sciatic nerve in mice. Expression of the mRNA of Trpa1 in murine dorsal-root-ganglion neurons was detected by RNAscope. Involvement of TRPA1 ion channels and SST₄ receptors was tested with gene-deleted animals. Macrophage activity at the site of the nerve lesion was determined by lucigenin bioluminescence. Density and activation of microglia in the spinal cord dorsal horn was verified by immunohistochemistry and image analysis. Trpa1 mRNA is expressed in peptidergic and non-peptidergic neurons in the dorsal root ganglion. DMTS ameliorated neuropathic pain in Trpa1 and Sstr4 WT mice, but not in KO ones. DMTS had no effect on macrophage activity around the damaged nerve. Microglial density in the dorsal horn was reduced by DMTS independently from TRPA1. No effect on microglial activation was detected. DMTS might offer a novel therapeutic opportunity in the complementary treatment of neuropathic pain. Full article

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

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20 pages, 11569 KiB

Open AccessArticle

Novel Genetically Modified Mouse Model to Assess Soman-Induced Toxicity and Medical Countermeasure Efficacy: Human Acetylcholinesterase Knock-in Serum Carboxylesterase Knockout Mice

by Brenda M. Marrero-Rosado, Michael F. Stone, Marcio de Araujo Furtado, Caroline R. Schultz, C. Linn Cadieux and Lucille A. Lumley

Int. J. Mol. Sci. 2021, 22(4), 1893; https://doi.org/10.3390/ijms22041893 - 14 Feb 2021

Cited by 6 | Viewed by 2662

Abstract

The identification of improved medical countermeasures against exposure to chemical warfare nerve agents (CWNAs), a class of organophosphorus compounds, is dependent on the choice of animal model used in preclinical studies. CWNAs bind to acetylcholinesterase and prevent the catalysis of acetylcholine, causing a [...] Read more.

The identification of improved medical countermeasures against exposure to chemical warfare nerve agents (CWNAs), a class of organophosphorus compounds, is dependent on the choice of animal model used in preclinical studies. CWNAs bind to acetylcholinesterase and prevent the catalysis of acetylcholine, causing a plethora of peripheral and central physiologic manifestations, including seizure. Rodents are widely used to elucidate the effects of CWNA-induced seizure, albeit with a caveat: they express carboxylesterase activity in plasma. Carboxylesterase, an enzyme involved in the detoxification of some organophosphorus compounds, plays a scavenging role and decreases CWNA availability, thus exerting a protective effect. Furthermore, species-specific amino acid differences in acetylcholinesterase confound studies that use oximes or other compounds to restore its function after inhibition by CWNA. The creation of a human acetylcholinesterase knock-in/serum carboxylesterase knockout (C57BL/6-Ces1c^tm1.1LocAChE^tm1.1Loc/J; a.k.a KIKO) mouse may facilitate better modeling of CWNA toxicity in a small rodent species. The current studies characterize the effects of exposure to soman, a highly toxic CWNA, and evaluate the efficacy of anti-seizure drugs in this newly developed KIKO mouse model. Data demonstrate that a combination of midazolam and ketamine reduces seizure duration and severity, eliminates the development of spontaneous recurrent seizures, and protects certain brain regions from neuronal damage in a genetically modified model with human relevance to organophosphorus compound toxicity. This new animal model and the results of this study and future studies using it will enhance medical countermeasures development for both defense and homeland security purposes. Full article

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

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20 pages, 5572 KiB

Open AccessArticle

Adaptive Thermogenesis in a Mouse Model Lacking Selenoprotein Biosynthesis in Brown Adipocytes

by Lucia A. Seale, Ashley N. Ogawa-Wong, Ligia M. Watanabe, Vedbar S. Khadka, Mark Menor, Daniel J. Torres, Bradley A. Carlson, Dolph L. Hatfield and Marla J. Berry

Int. J. Mol. Sci. 2021, 22(2), 611; https://doi.org/10.3390/ijms22020611 - 9 Jan 2021

Cited by 5 | Viewed by 3191

Abstract

Selenoproteins are a class of proteins with the selenium-containing amino acid selenocysteine (Sec) in their primary structure. Sec is incorporated into selenoproteins via recoding of the stop codon UGA, with specific cis and trans factors required during translation to avoid UGA recognition as [...] Read more.

Selenoproteins are a class of proteins with the selenium-containing amino acid selenocysteine (Sec) in their primary structure. Sec is incorporated into selenoproteins via recoding of the stop codon UGA, with specific cis and trans factors required during translation to avoid UGA recognition as a stop codon, including a Sec-specific tRNA, tRNA^[Ser]Sec, encoded in mice by the gene Trsp. Whole-body deletion of Trsp in mouse is embryonically lethal, while targeted deletion of Trsp in mice has been used to understand the role of selenoproteins in the health and physiology of various tissues. We developed a mouse model with the targeted deletion of Trsp in brown adipocytes (Trsp^f/f-Ucp1-Cre^+/−), a cell type predominant in brown adipose tissue (BAT) controlling energy expenditure via activation of adaptive thermogenesis, mostly using uncoupling protein 1 (Ucp1). At room temperature, Trsp^f/f-Ucp1-Cre^+/− mice maintain oxygen consumption and Ucp1 expression, with male Trsp^f/f-Ucp1-Cre^+/− mice accumulating more triglycerides in BAT than both female Trsp^f/f-Ucp1-Cre^+/− mice or Trsp^f/f controls. Acute cold exposure neither reduced core body temperature nor changed the expression of selenoprotein iodothyronine deiodinase type II (Dio2), a marker of adaptive thermogenesis, in Trsp^f/f-Ucp1-Cre^+/− mice. Microarray analysis of BAT from Trsp^f/f-Ucp1-Cre^+/− mice revealed glutathione S-transferase alpha 3 (Gsta3) and ELMO domain containing 2 (Elmod2) as the transcripts most affected by the loss of Trsp. Male Trsp^f/f-Ucp1-Cre^+/− mice showed mild hypothyroidism while downregulating thyroid hormone-responsive genes Thrsp and Tshr in their BATs. In summary, modest changes in the BAT of Trsp^f/f-Ucp1-Cre ^+/− mice implicate a mild thyroid hormone dysfunction in brown adipocytes. Full article

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

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22 pages, 5148 KiB

Open AccessArticle

Molecular Characterization of Constipation Disease as Novel Phenotypes in CRISPR-Cas9-Generated Leptin Knockout Mice with Obesity

by Ji Eun Kim, Yun Ju Choi, Su Jin Lee, Jeong Eun Gong, Yong Lim, Jin Tae Hong and Dae Youn Hwang

Int. J. Mol. Sci. 2020, 21(24), 9464; https://doi.org/10.3390/ijms21249464 - 12 Dec 2020

Cited by 11 | Viewed by 3020

Abstract

(1) Background: We characterized a novel animal model with obesity-induced constipation because constipation is rarely known in genetically engineered mice (GEM); (2) Methods: The changes in the constipation parameters and mechanisms were analyzed in CRISPR-Cas9-mediated leptin (Lep) knockout (KO) mice from eight to [...] Read more.

(1) Background: We characterized a novel animal model with obesity-induced constipation because constipation is rarely known in genetically engineered mice (GEM); (2) Methods: The changes in the constipation parameters and mechanisms were analyzed in CRISPR-Cas9-mediated leptin (Lep) knockout (KO) mice from eight to 24 weeks; (3) Results: Significant constipation phenotypes were observed in the Lep KO mice since 16 weeks old. These mice showed a significant decrease in the gastrointestinal motility, mucosal layer thickness and ability for mucin secretion as well as the abnormal ultrastructure of Lieberkühn crypts in the transverse colon. The density or function of the enteric neurons, intestinal Cajal cells (ICC), smooth muscle cells, and the concentration of gastrointestinal (GI) hormones for the GI motility were remarkably changed in Lep KO mice. The downstream signaling pathway of muscarinic acetylcholine receptors (mAChRs) were activated in Lep KO mice, while the expression of adipogenesis-regulating genes were alternatively reduced in the transverse colon of the same mice; (4) Conclusions: These results provide the first strong evidence that Lep KO mice can represent constipation successfully through dysregulation of the GI motility mediated by myenteric neurons, ICC, and smooth muscle cells in the transverse colon during an abnormal function of the lipid metabolism. Full article

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

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14 pages, 1904 KiB

Open AccessArticle

Phytohormone Abscisic Acid Improves Memory Impairment and Reduces Neuroinflammation in 5xFAD Mice by Upregulation of LanC-Like Protein 2

by Seung Ho Jeon, Namkwon Kim, Yeon-Joo Ju, Min Sung Gee, Danbi Lee and Jong Kil Lee

Int. J. Mol. Sci. 2020, 21(22), 8425; https://doi.org/10.3390/ijms21228425 - 10 Nov 2020

Cited by 16 | Viewed by 2753

Abstract

Alzheimer’s disease (AD), a type of dementia, is the most common neurodegenerative disease in the elderly. Neuroinflammation caused by deposition of amyloid β (Aβ) is one of the most important pathological causes in AD. The isoprenoid phytohormone abscisic acid (ABA) has recently been [...] Read more.

Alzheimer’s disease (AD), a type of dementia, is the most common neurodegenerative disease in the elderly. Neuroinflammation caused by deposition of amyloid β (Aβ) is one of the most important pathological causes in AD. The isoprenoid phytohormone abscisic acid (ABA) has recently been found in mammals and was shown to be an endogenous hormone, acting in stress conditions. Although ABA has been associated with anti-inflammatory effects and reduced cognitive impairment in several studies, the mechanisms of ABA in AD has not been ascertained clearly. To investigate the clearance of Aβ and anti-inflammatory effects of ABA, we used quantitative real-time polymerase chain reaction and immunoassay. ABA treatment inhibited Aβ deposition and neuroinflammation, thus resulting in improvement of memory impairment in 5xFAD mice. Interestingly, these effects were not associated with activation of peroxisome proliferator-activated receptor gamma, well known as a molecular target of ABA, but related with modulation of the LanC-like protein 2 (LANCL2), known as a receptor of ABA. Taken together, our results indicate that ABA reduced Aβ deposition, neuroinflammation, and memory impairment, which is the most characteristic pathology of AD, via the upregulation of LANCL2. These data suggest that ABA might be a candidate for therapeutics for AD treatment. Full article

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

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11 pages, 1354 KiB

Open AccessArticle

Neuropeptide Y as Alternative Pharmacotherapy for Antidepressant-Resistant Social Fear

by Johannes Kornhuber and Iulia Zoicas

Int. J. Mol. Sci. 2020, 21(21), 8220; https://doi.org/10.3390/ijms21218220 - 3 Nov 2020

Cited by 6 | Viewed by 1915

Abstract

In many social anxiety disorder (SAD) patients, the efficacy of antidepressant therapy is unsatisfactory. Here, we investigated whether mice deficient for the lysosomal glycoprotein acid sphingomyelinase (ASM−/−) represent an appropriate tool to study antidepressant-resistant social fear. We also investigated whether neuropeptide Y (NPY) [...] Read more.

In many social anxiety disorder (SAD) patients, the efficacy of antidepressant therapy is unsatisfactory. Here, we investigated whether mice deficient for the lysosomal glycoprotein acid sphingomyelinase (ASM−/−) represent an appropriate tool to study antidepressant-resistant social fear. We also investigated whether neuropeptide Y (NPY) reduces this antidepressant-resistant social fear in ASM−/− mice, given that NPY reduced social fear in a mouse model of SAD, namely social fear conditioning (SFC). We show that neither chronic paroxetine nor chronic amitriptyline administration via drinking water were successful in reducing SFC-induced social fear in ASM−/− mice, while the same treatment reduced social fear in ASM+/− mice and completely reversed social fear in ASM+/+ mice. This indicates that the antidepressants paroxetine and amitriptyline reduce social fear via the ASM-ceramide system and that ASM−/− mice represent an appropriate tool to study antidepressant-resistant social fear. The intracerebroventricular administration of NPY, on the other hand, reduced social fear in ASM−/− mice, suggesting that NPY might represent an alternative pharmacotherapy for antidepressant-resistant social fear. These results suggest that medication strategies aimed at increasing brain NPY concentrations might improve symptoms of social fear in SAD patients who fail to respond to antidepressant treatments. Full article

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

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17 pages, 3091 KiB

Open AccessArticle

Dnmt3a2/Dnmt3L Overexpression in the Dopaminergic System of Mice Increases Exercise Behavior through Signaling Changes in the Hypothalamus

by Di Cui, Andrea Mesaros, Gregor Burdeos, Ingo Voigt, Patrick Giavalisco, Yvonne Hinze, Martin Purrio, Bernd Neumaier, Alexander Drzezga, Yayoi Obata, Heike Endepols and Xiangru Xu

Int. J. Mol. Sci. 2020, 21(17), 6297; https://doi.org/10.3390/ijms21176297 - 31 Aug 2020

Cited by 5 | Viewed by 3221

Abstract

Dnmt3a2, a de novo DNA methyltransferase, is induced by neuronal activity and participates in long-term memory formation with the increased expression of synaptic plasticity genes. We wanted to determine if Dnmt3a2 with its partner Dnmt3L may influence motor behavior via the dopaminergic system. [...] Read more.

Dnmt3a2, a de novo DNA methyltransferase, is induced by neuronal activity and participates in long-term memory formation with the increased expression of synaptic plasticity genes. We wanted to determine if Dnmt3a2 with its partner Dnmt3L may influence motor behavior via the dopaminergic system. To this end, we generated a mouse line, Dnmt3a2/3L^Dat^/wt, with dopamine transporter (DAT) promotor driven Dnmt3a2/3L overexpression. The mice were studied with behavioral paradigms (e.g., cylinder test, open field, and treadmill), brain slice patch clamp recordings, ex vivo metabolite analysis, and in vivo positron emission tomography (PET) using the dopaminergic tracer 6-[¹⁸F]FMT. The results showed that spontaneous activity and exercise performance were enhanced in Dnmt3a2/3L^Dat^/wt mice compared to Dnmt3a2/3L^wt^/wt controls. Dopaminergic substantia nigra pars compacta neurons of Dnmt3a2/3L^Dat^/wt animals displayed a higher fire frequency and excitability. However, dopamine concentration was not increased in the striatum, and dopamine metabolite concentration was even significantly decreased. Striatal 6-[¹⁸F]FMT uptake, reflecting aromatic L-amino acid decarboxylase activity, was the same in Dnmt3a2/3L^Dat^/wt mice and controls. [¹⁸F]FDG PET showed that hypothalamic metabolic activity was tightly linked to motor behavior in Dnmt3a2/3L^Dat^/wt mice. Furthermore, dopamine biosynthesis and motor-related metabolic activity were correlated in the hypothalamus. Our findings suggest that Dnmt3a2/3L, when overexpressed in dopaminergic neurons, modulates motor performance via activation of the nigrostriatal pathway. This does not involve increased dopamine synthesis. Full article

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

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9 pages, 1193 KiB

Open AccessCommunication

IDH2 Deficiency Is Critical in Myogenesis and Fatty Acid Metabolism in Mice Skeletal Muscle

by Jeong Hoon Pan, Jingsi Tang, Young Jun Kim, Jin Hyup Lee, Eui-Cheol Shin, Jiangchao Zhao, Kee-Hong Kim, Kyung A. Hwang, Yan Huang and Jae Kyeom Kim

Int. J. Mol. Sci. 2020, 21(16), 5596; https://doi.org/10.3390/ijms21165596 - 5 Aug 2020

Cited by 4 | Viewed by 3020

Abstract

Mitochondrial NADP⁺-dependent isocitrate dehydrogenase (IDH2) catalyzes the oxidative decarboxylation of isocitrate into α-ketoglutarate with concurrent reduction of NADP⁺ to NADPH. However, it is not fully understood how IDH2 is intertwined with muscle development and fatty acid metabolism. Here, we examined [...] Read more.

Mitochondrial NADP⁺-dependent isocitrate dehydrogenase (IDH2) catalyzes the oxidative decarboxylation of isocitrate into α-ketoglutarate with concurrent reduction of NADP⁺ to NADPH. However, it is not fully understood how IDH2 is intertwined with muscle development and fatty acid metabolism. Here, we examined the effects of IDH2 knockout (KO) on skeletal muscle energy homeostasis. Calf skeletal muscle samples from 10-week-old male IDH2 KO and wild-type (WT; C57BL/6N) mice were harvested, and the ratio of skeletal muscle weight to body and the ratio of mitochondrial to nucleic DNA were measured. In addition, genes involved in myogenesis, mitochondria biogenesis, adipogenesis, and thermogenesis were compared. Results showed that the ratio of skeletal muscle weight to body weight was lower in IDH2 KO mice than those in WT mice. Of note, a noticeable shift in fiber size distribution was found in IDH2 KO mice. Additionally, there was a trend of a decrease in mitochondrial content in IDH2 KO mice than in WT mice (p = 0.09). Further, mRNA expressions for myogenesis and mitochondrial biogenesis were either decreased or showed a trend of decrease in IDH2 KO mice. Moreover, genes for adipogenesis pathway (Pparg, Znf423, and Fat1) were downregulated in IDH2 KO mice. Interestingly, mRNA and protein expression of uncoupling protein 1 (UCP1), a hallmark of thermogenesis, were remarkably increased in IDH2 KO mice. In line with the UCP1 expression, IDH2 KO mice showed higher rectal temperature than WT mice under cold stress. Taken together, IDH2 deficiency may affect myogenesis, possibly due to impairments of muscle generation and abnormal fatty acid oxidation as well as thermogenesis in muscle via upregulation of UCP1. Full article

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

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12 pages, 3991 KiB

Open AccessArticle

Winnie-APC^Min/+ Mice: A Spontaneous Model of Colitis-Associated Colorectal Cancer Combining Genetics and Inflammation

by Stefania De Santis, Giulio Verna, Grazia Serino, Raffaele Armentano, Elisabetta Cavalcanti, Marina Liso, Manuela Dicarlo, Sergio Coletta, Mauro Mastronardi, Antonio Lippolis, Angela Tafaro, Angelo Santino, Aldo Pinto, Pietro Campiglia, Alex Y. Huang, Fabio Cominelli, Theresa T. Pizarro and Marcello Chieppa

Int. J. Mol. Sci. 2020, 21(8), 2972; https://doi.org/10.3390/ijms21082972 - 23 Apr 2020

Cited by 10 | Viewed by 4993

Abstract

(1) Background: Colorectal cancer (CRC) is among the best examples of the relationship between inflammation and increased cancer risk. (2) Methods: To examine the effects of spontaneous low-grade chronic inflammation on the pathogenesis of CRC, we developed a new murine model of colitis-associated [...] Read more.

(1) Background: Colorectal cancer (CRC) is among the best examples of the relationship between inflammation and increased cancer risk. (2) Methods: To examine the effects of spontaneous low-grade chronic inflammation on the pathogenesis of CRC, we developed a new murine model of colitis-associated cancer (CAC) by crossing Mucin 2 mutated mice (Winnie) with Apc^Min/+ mice. (3) Results: The resulting Winnie-Apc^Min/+ model combines an inflammatory background with a genetic predisposition to small intestinal polyposis. Winnie-Apc^Min/+ mice show an early occurrence of inflammatory signs and dysplastic lesions in the distal colon with a specific molecular signature. (4) Conclusion: The Winnie-Apc^Min/+ model is a perfect model to demonstrate that chronic inflammation represents a crucial risk factor for the onset and progression of tumoral lesions in individuals genetically predisposed to CRC. Full article

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

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Review

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26 pages, 643 KiB

Open AccessReview

A Comprehensive Review of Genetically Engineered Mouse Models for Prader-Willi Syndrome Research

by Delf-Magnus Kummerfeld, Carsten A. Raabe, Juergen Brosius, Dingding Mo, Boris V. Skryabin and Timofey S. Rozhdestvensky

Int. J. Mol. Sci. 2021, 22(7), 3613; https://doi.org/10.3390/ijms22073613 - 31 Mar 2021

Cited by 15 | Viewed by 5185

Abstract

Prader-Willi syndrome (PWS) is a neurogenetic multifactorial disorder caused by the deletion or inactivation of paternally imprinted genes on human chromosome 15q11-q13. The affected homologous locus is on mouse chromosome 7C. The positional conservation and organization of genes including the imprinting pattern between [...] Read more.

Prader-Willi syndrome (PWS) is a neurogenetic multifactorial disorder caused by the deletion or inactivation of paternally imprinted genes on human chromosome 15q11-q13. The affected homologous locus is on mouse chromosome 7C. The positional conservation and organization of genes including the imprinting pattern between mice and men implies similar physiological functions of this locus. Therefore, considerable efforts to recreate the pathogenesis of PWS have been accomplished in mouse models. We provide a summary of different mouse models that were generated for the analysis of PWS and discuss their impact on our current understanding of corresponding genes, their putative functions and the pathogenesis of PWS. Murine models of PWS unveiled the contribution of each affected gene to this multi-facetted disease, and also enabled the establishment of the minimal critical genomic region (PWScr) responsible for core symptoms, highlighting the importance of non-protein coding genes in the PWS locus. Although the underlying disease-causing mechanisms of PWS remain widely unresolved and existing mouse models do not fully capture the entire spectrum of the human PWS disorder, continuous improvements of genetically engineered mouse models have proven to be very powerful and valuable tools in PWS research. Full article

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

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67 pages, 1357 KiB

Open AccessReview

Annexin Animal Models—From Fundamental Principles to Translational Research

by Thomas Grewal, Carles Rentero, Carlos Enrich, Mohamed Wahba, Carsten A. Raabe and Ursula Rescher

Int. J. Mol. Sci. 2021, 22(7), 3439; https://doi.org/10.3390/ijms22073439 - 26 Mar 2021

Cited by 35 | Viewed by 4899

Abstract

Routine manipulation of the mouse genome has become a landmark in biomedical research. Traits that are only associated with advanced developmental stages can now be investigated within a living organism, and the in vivo analysis of corresponding phenotypes and functions advances the translation [...] Read more.

Routine manipulation of the mouse genome has become a landmark in biomedical research. Traits that are only associated with advanced developmental stages can now be investigated within a living organism, and the in vivo analysis of corresponding phenotypes and functions advances the translation into the clinical setting. The annexins, a family of closely related calcium (Ca²⁺)- and lipid-binding proteins, are found at various intra- and extracellular locations, and interact with a broad range of membrane lipids and proteins. Their impacts on cellular functions has been extensively assessed in vitro, yet annexin-deficient mouse models generally develop normally and do not display obvious phenotypes. Only in recent years, studies examining genetically modified annexin mouse models which were exposed to stress conditions mimicking human disease often revealed striking phenotypes. This review is the first comprehensive overview of annexin-related research using animal models and their exciting future use for relevant issues in biology and experimental medicine. Full article

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

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12 pages, 287 KiB

Open AccessReview

TCR Transgenic Mice: A Valuable Tool for Studying Viral Immunopathogenesis Mechanisms

by Yong-Bin Cho, In-Gu Lee, Yong-Hyun Joo, So-Hee Hong and Young-Jin Seo

Int. J. Mol. Sci. 2020, 21(24), 9690; https://doi.org/10.3390/ijms21249690 - 18 Dec 2020

Cited by 6 | Viewed by 7228

Abstract

Viral infectious diseases are a significant burden on public health and the global economy, and new viral threats emerge continuously. Since CD4⁺ and CD8⁺ T cell responses are essential to eliminating viruses, it is important to understand the underlying mechanisms of [...] Read more.

Viral infectious diseases are a significant burden on public health and the global economy, and new viral threats emerge continuously. Since CD4⁺ and CD8⁺ T cell responses are essential to eliminating viruses, it is important to understand the underlying mechanisms of anti-viral T cell-mediated immunopathogenesis during viral infections. Remarkable progress in transgenic (Tg) techniques has enabled scientists to more readily understand the mechanisms of viral pathogenesis. T cell receptor (TCR) Tg mice are extremely useful in studying T cell-mediated immune responses because the majority of T cells in these mice express specific TCRs for partner antigens. In this review, we discuss the important studies utilizing TCR Tg mice to unveil underlying mechanisms of T cell-mediated immunopathogenesis during viral infections. Full article

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

20 pages, 805 KiB

Open AccessReview

Advances in Transgenic Mouse Models to Study Infections by Human Pathogenic Viruses

by Dörthe Masemann, Stephan Ludwig and Yvonne Boergeling

Int. J. Mol. Sci. 2020, 21(23), 9289; https://doi.org/10.3390/ijms21239289 - 5 Dec 2020

Cited by 18 | Viewed by 8198

Abstract

Medical research is changing into direction of precision therapy, thus, sophisticated preclinical models are urgently needed. In human pathogenic virus research, the major technical hurdle is not only to translate discoveries from animals to treatments of humans, but also to overcome the problem [...] Read more.

Medical research is changing into direction of precision therapy, thus, sophisticated preclinical models are urgently needed. In human pathogenic virus research, the major technical hurdle is not only to translate discoveries from animals to treatments of humans, but also to overcome the problem of interspecies differences with regard to productive infections and comparable disease development. Transgenic mice provide a basis for research of disease pathogenesis after infection with human-specific viruses. Today, humanized mice can be found at the very heart of this forefront of medical research allowing for recapitulation of disease pathogenesis and drug mechanisms in humans. This review discusses progress in the development and use of transgenic mice for the study of virus-induced human diseases towards identification of new drug innovations to treat and control human pathogenic infectious diseases. Full article

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

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41 pages, 868 KiB

Open AccessReview

From Mice to Humans: An Overview of the Potentials and Limitations of Current Transgenic Mouse Models of Major Muscular Dystrophies and Congenital Myopathies

by Mónika Sztretye, László Szabó, Nóra Dobrosi, János Fodor, Péter Szentesi, János Almássy, Zsuzsanna É. Magyar, Beatrix Dienes and László Csernoch

Int. J. Mol. Sci. 2020, 21(23), 8935; https://doi.org/10.3390/ijms21238935 - 25 Nov 2020

Cited by 12 | Viewed by 4761

Abstract

Muscular dystrophies are a group of more than 160 different human neuromuscular disorders characterized by a progressive deterioration of muscle mass and strength. The causes, symptoms, age of onset, severity, and progression vary depending on the exact time point of diagnosis and the [...] Read more.

Muscular dystrophies are a group of more than 160 different human neuromuscular disorders characterized by a progressive deterioration of muscle mass and strength. The causes, symptoms, age of onset, severity, and progression vary depending on the exact time point of diagnosis and the entity. Congenital myopathies are rare muscle diseases mostly present at birth that result from genetic defects. There are no known cures for congenital myopathies; however, recent advances in gene therapy are promising tools in providing treatment. This review gives an overview of the mouse models used to investigate the most common muscular dystrophies and congenital myopathies with emphasis on their potentials and limitations in respect to human applications. Full article

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

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19 pages, 1617 KiB

Open AccessReview

Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models

by Oliver Wirths and Silvia Zampar

Int. J. Mol. Sci. 2020, 21(21), 8144; https://doi.org/10.3390/ijms21218144 - 30 Oct 2020

Cited by 44 | Viewed by 5168

Abstract

Transgenic mouse models represent an essential tool for the exploration of Alzheimer’s disease (AD) pathological mechanisms and the development of novel treatments, which at present provide only symptomatic and transient effects. While a variety of mouse models successfully reflects the main neuropathological hallmarks [...] Read more.

Transgenic mouse models represent an essential tool for the exploration of Alzheimer’s disease (AD) pathological mechanisms and the development of novel treatments, which at present provide only symptomatic and transient effects. While a variety of mouse models successfully reflects the main neuropathological hallmarks of AD, such as extracellular amyloid-β (Aβ) deposits, intracellular accumulation of Tau protein, the development of micro- and astrogliosis, as well as behavioral deficits, substantial neuron loss, as a key feature of the disease, seems to be more difficult to achieve. In this review, we summarize information on classic and more recent transgenic mouse models for AD, focusing in particular on loss of pyramidal, inter-, and cholinergic neurons. Although the cause of neuron loss in AD is still a matter of scientific debate, it seems to be linked to intraneuronal Aβ accumulation in several transgenic mouse models, especially in pyramidal neurons. Full article

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

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14 pages, 550 KiB

Open AccessReview

Cell Fate Determination of Lymphatic Endothelial Cells

by Young Jae Lee

Int. J. Mol. Sci. 2020, 21(13), 4790; https://doi.org/10.3390/ijms21134790 - 6 Jul 2020

Cited by 6 | Viewed by 4707

Abstract

The lymphatic vasculature, along with the blood vasculature, is a vascular system in our body that plays important functions in fluid homeostasis, dietary fat uptake, and immune responses. Defects in the lymphatic system are associated with various diseases such as lymphedema, atherosclerosis, fibrosis, [...] Read more.

The lymphatic vasculature, along with the blood vasculature, is a vascular system in our body that plays important functions in fluid homeostasis, dietary fat uptake, and immune responses. Defects in the lymphatic system are associated with various diseases such as lymphedema, atherosclerosis, fibrosis, obesity, and inflammation. The first step in lymphangiogenesis is determining the cell fate of lymphatic endothelial cells. Several genes involved in this commitment step have been identified using animal models, including genetically modified mice. This review provides an overview of these genes in the mammalian system and related human diseases. Full article

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

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