Sign in to use this feature.

Years

Between: -

Subjects

remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline

Journals

Article Types

Countries / Regions

Search Results (172)

Search Parameters:
Keywords = knockin mice

Order results
Result details
Results per page
Select all
Export citation of selected articles as:
21 pages, 8286 KiB  
Article
Conditional Overexpression of Neuritin in Supporting Cell Protects Cochlear Hair Cell and Delays Age-Related Hearing Loss by Enhancing Autophagy
by Shanshan Wang, Shaowei Lv, Junhao Hu, Yunfan Shi, Yu Li, Jianyun Zhang, Xiaohua Tan, Rong Chen and Yu Hong
Int. J. Mol. Sci. 2025, 26(8), 3709; https://doi.org/10.3390/ijms26083709 - 14 Apr 2025
Viewed by 217
Abstract
Age-related hearing loss (ARHL) is a highly prevalent, burdensome sensorineural hearing loss closely associated with impaired autophagic influx. Our previous studies revealed that neuritin, a neurotrophic factor primarily expressed in the central nervous system, could alleviate drug-induced damages in hair cells (HCs) and [...] Read more.
Age-related hearing loss (ARHL) is a highly prevalent, burdensome sensorineural hearing loss closely associated with impaired autophagic influx. Our previous studies revealed that neuritin, a neurotrophic factor primarily expressed in the central nervous system, could alleviate drug-induced damages in hair cells (HCs) and spiral ganglion neurons. However, its effects on ARHL and whether these effects are closely related to autophagy remain unclear. Using the Nrn1 knock-in mice and cultured cochlear basilar membrane (CBM) of the neonatal mouse, we show that neuritin could restore aging-associated hearing loss and alleviate senescence-associated damage in the cochlea. Overexpression of neuritin in support cells (SCs) alleviates the loss of cochlear HCs and nerve fibers, reducing the damage to spiral ganglion neurons and the shifts in ABR’s high-frequency threshold. Furthermore, conditional overexpression of neuritin in SCs improves autophagic influx by upregulating the expression of microtubule-associated protein 1 light chain 3 type B (LCB3) protein and downregulating the expression of p21 protein. In cultured neonatal mouse CBM, neuritin administration significantly inhibits D-galactose-induced HC loss, cellular apoptosis, and ROS production and promotes autophagic influx. These effects were weakened when the autophagy inhibitor 3-MA was added. In summary, our results confirm the therapeutic potential of neuritin treatment for ARHL. Full article
(This article belongs to the Section Molecular Neurobiology)
Show Figures

Figure 1

20 pages, 2381 KiB  
Article
Environmental Factors Exacerbate Parkinsonian Phenotypes in an Asian-Specific Knock-In LRRK2 Risk Variant in Mice
by Zoë Bichler, Sarivin Vanan, Zhiwei Zhang, Qianying (Sally) Dong, Jolene Wei Ling Lee, Chengwu Zhang, Liting Hang, Mei Jiang, Parasuraman Padmanabhan, Wuan Ting Saw, Zhidong Zhou, Balázs Gulyás, Kah Leong Lim, Li Zeng and Eng King Tan
Int. J. Mol. Sci. 2025, 26(8), 3556; https://doi.org/10.3390/ijms26083556 - 10 Apr 2025
Viewed by 229
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder affecting nearly 10 million people worldwide, and for which no cure is currently known. Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene, age, as well as environmental factors such as neurotoxin exposure and stress, are [...] Read more.
Parkinson’s disease (PD) is a neurodegenerative disorder affecting nearly 10 million people worldwide, and for which no cure is currently known. Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene, age, as well as environmental factors such as neurotoxin exposure and stress, are known to increase the risk of developing the disease in humans. To investigate the role of a specific Asian variant of the LRRK2 gene to induce susceptibility to stress and trigger PD phenotypes with time, knock-in (KI) mice bearing the human LRRK2 R1628P risk variant have been generated and studied from 2 to 16 months of age in the presence (or absence) of stress insults, including neurotoxin injections and chronic mild stress applied at 3 months of age. Pathophysiological and behavioural phenotypes have been measured at different ages and primary neurons and fibroblast cells were cultured from the KI mouse line and treated with H2O2 to study susceptibility towards oxidative stress in vitro. KI mice displayed specific PD features and these phenotypes were aggravated by environmental stresses. In particular, KI mice developed locomotion impairment and increased constipation. In addition, dopamine-related proteins were dysregulated in KI mice brains: Dopamine transporter (DAT) was decreased in the midbrain and striatum and dopamine levels were increased. Primary fibroblast cells and cortical neurons from KI mice also displayed increased susceptibility to oxidative stress. Therefore, the LRRK2 R1628P KI mice are an excellent model to study the progressive development of PD. Full article
Show Figures

Figure 1

20 pages, 8925 KiB  
Article
A New Human SCARB2 Knock-In Mouse Model for Studying Coxsackievirus A16 and Its Neurotoxicity
by Haiting Wu, Ziou Wang, Yiwei Zhang, Lingfeng Hu, Jinling Yang, Caixing Zhang, Mumeng Lou, Na Pi, Qiyan Wang, Shengtao Fan and Zhangqiong Huang
Viruses 2025, 17(3), 423; https://doi.org/10.3390/v17030423 - 14 Mar 2025
Viewed by 494
Abstract
Hand, Foot, and Mouth Disease (HFMD) is a viral illness caused by enterovirus infections. While the introduction of the enterovirus 71 (EV71) vaccine has significantly reduced the number of EV71-related cases, the continued spread of Coxsackievirus A16 (CVA16) remains a major public health [...] Read more.
Hand, Foot, and Mouth Disease (HFMD) is a viral illness caused by enterovirus infections. While the introduction of the enterovirus 71 (EV71) vaccine has significantly reduced the number of EV71-related cases, the continued spread of Coxsackievirus A16 (CVA16) remains a major public health threat. Previous studies have shown that human SCARB2 (hSCARB2) knock-in (KI) mice, generated using embryonic stem cell (ESC) technology, are susceptible to CVA16. However, these models have failed to reproduce the clinical pathology and neurotoxicity after CVA16 infection. Therefore, there is an urgent need for a more reliable and effective animal model to study CVA16. In this study, we successfully created a hSCARB2 KI mouse model targeting the ROSA26 locus using CRISPR/Cas9 gene editing technology. The application of CRISPR/Cas9 enabled stable and widespread expression of hSCARB2 in the model. After infection, the KI mice exhibited a clinical pathology that closely mimics human infection, with prominent limb weakness and paralysis. The virus was detectable in multiple major organs of the mice, with peak viral load observed on day 7 post-infection, gradually clearing thereafter. Further analysis revealed widespread neuronal necrosis and infiltration of inflammatory cells in the brain and spinal cord of the KI mice. Additionally, significant activation of astrocytes (GFAP-positive) and microglia (IBA1-positive) was observed in the brain, suggesting that CVA16 infection may induce limb paralysis by attacking neuronal cells. Overall, this model effectively replicates the neuropathological changes induced by CVA16 infection and provides a potential experimental platform for studying CVA16-associated pathogenesis and neurotoxicity. Full article
(This article belongs to the Section Human Virology and Viral Diseases)
Show Figures

Figure 1

16 pages, 2890 KiB  
Article
Sex Differences in a Novel Mouse Model of Spinocerebellar Ataxia Type 1 (SCA1)
by Adem Selimovic, Kaelin Sbrocco, Gourango Talukdar, Adri McCall, Stephen Gilliat, Ying Zhang and Marija Cvetanovic
Int. J. Mol. Sci. 2025, 26(6), 2623; https://doi.org/10.3390/ijms26062623 - 14 Mar 2025
Viewed by 549
Abstract
Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant inherited neurodegenerative disease caused by the expansion of glutamine (Q)-encoding CAG repeats in the gene ATAXIN1 (ATXN1). Patients with SCA1 suffer from movement and cognitive deficits and severe cerebellar pathology. Previous [...] Read more.
Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant inherited neurodegenerative disease caused by the expansion of glutamine (Q)-encoding CAG repeats in the gene ATAXIN1 (ATXN1). Patients with SCA1 suffer from movement and cognitive deficits and severe cerebellar pathology. Previous studies identified sex differences in disease progression in SCA1 patients, but whether these differences are present in mouse models is unclear. Using a battery of behavioral tests, immunohistochemistry of brain slices, and RNA sequencing, we examined sex differences in motor and cognitive performance, cerebellar pathology, and cerebellar gene expression changes in a recently created conditional knock-in mouse model f-ATXN1146Q expressing human coding regions of ATXN1 with 146 CAG repeats. We found worse motor performance and weight loss accompanied by increased microglial activation and an increase in immune viral response pathways in male f-ATXN1146Q mice. Full article
Show Figures

Figure 1

17 pages, 30120 KiB  
Article
Functional Investigation of a Novel PIWIL4 Mutation in Nonobstructive Azoospermia During the First Wave of Spermatogenesis
by Xiayu Wang, Qian Du, Wanqian Li, Zhongyu Zou, Chikun Wang, Yan Zhou, Zhibin Hu, Yayun Gu and Feng Li
Biomolecules 2025, 15(2), 297; https://doi.org/10.3390/biom15020297 - 17 Feb 2025
Viewed by 726
Abstract
PIWI-interacting RNAs (piRNAs) are small noncoding RNAs that are almost exclusively expressed in germ cells to silence harmful transposons to maintain genome stability. PIWIL4 is guided by its associated piRNAs to transposable elements, where it recruits the DNA methylation apparatus and instructs de [...] Read more.
PIWI-interacting RNAs (piRNAs) are small noncoding RNAs that are almost exclusively expressed in germ cells to silence harmful transposons to maintain genome stability. PIWIL4 is guided by its associated piRNAs to transposable elements, where it recruits the DNA methylation apparatus and instructs de novo DNA methylation. Herein, we identified a missense variant of PIWIL4 (c.805 C>T p.R269W) in two infertile males. Homozygous male mice carrying the orthologous knock-in variant displayed elevated transposable element expression and aberrant gene expression during the first wave of spermatogenesis, despite exhibiting normal sperm counts and morphology. Mechanistically, the mutated site altered the piRNA-binding ability of PIWIL4 and led to the derepression of endogenous LINE-1 elements. In summary, we identified a piRNA binding mutation in PIWIL4 that may be involved in human nonobstructive azoospermia. Full article
(This article belongs to the Collection Feature Papers in Molecular Reproduction)
Show Figures

Figure 1

19 pages, 20178 KiB  
Article
Cardiac MRI Strain as an Early Indicator of Myocardial Dysfunction in Hypertrophic Cardiomyopathy
by Siqin Liu, Oumaima Laghzali, Shahriar Shalikar, Mara-Camelia Rusu, Lucie Carrier, Thoralf Niendorf and Min-Chi Ku
Int. J. Mol. Sci. 2025, 26(4), 1407; https://doi.org/10.3390/ijms26041407 - 7 Feb 2025
Cited by 1 | Viewed by 875
Abstract
Hypertrophic cardiomyopathy (HCM) is often characterized by augmented cardiac contractility, which frequently remains undetectable in its early stages. Emerging evidence suggests that hypercontractility is linked to mitochondrial defects that develop early in HCM progression. However, imaging markers for identifying these early alterations in [...] Read more.
Hypertrophic cardiomyopathy (HCM) is often characterized by augmented cardiac contractility, which frequently remains undetectable in its early stages. Emerging evidence suggests that hypercontractility is linked to mitochondrial defects that develop early in HCM progression. However, imaging markers for identifying these early alterations in myocardial function are lacking. We used cardiac magnetic resonance feature tracking (CMR-FT) to assess myocardial strain in a Mybpc3-knockin (KI) mouse model that mimicked human HCM. While homozygous (HOM) mice exhibited cardiac hypertrophy, heterozygous (HET) mice represented an early, asymptomatic stage of HCM. To explore mitochondrial contributions to hypercontractility, we evaluated mitochondrial integrity via scanning electron microscopy (SEM) and correlated these findings with strain abnormalities. Young HET female, but not male mice exhibited significant torsion abnormalities (p = 0.02), reduced left ventricular global longitudinal strain (LVGLS, p = 0.009), and impaired right ventricular global longitudinal strain (RVGLS, p = 0.035) compared to the controls. Strain abnormalities correlated strongly with mitochondrial morphological alterations, including changes in volume and area distribution (R > 0.7). Abnormal myocardial strain patterns, including torsion and GLS, serve as early markers of HCM and are closely associated with underlying mitochondrial dysfunction. The HET Mybpc3-KI HCM model provides important insights into the initial stages of HCM progression, highlighting strain abnormalities and sex-specific differences to enhance early diagnosis and therapeutic strategies. Full article
Show Figures

Figure 1

20 pages, 7853 KiB  
Article
RTL4, a Retrovirus-Derived Gene Implicated in Autism Spectrum Disorder, Is a Microglial Gene That Responds to Noradrenaline in the Postnatal Brain
by Fumitoshi Ishino, Johbu Itoh, Ayumi Matsuzawa, Masahito Irie, Toru Suzuki, Yuichi Hiraoka, Masanobu Yoshikawa and Tomoko Kaneko-Ishino
Int. J. Mol. Sci. 2024, 25(24), 13738; https://doi.org/10.3390/ijms252413738 - 23 Dec 2024
Viewed by 1178
Abstract
Retrotransposon Gag-like 4 (RTL4), a gene acquired from a retrovirus, is a causative gene in autism spectrum disorder. Its knockout mice exhibit increased impulsivity, impaired short-term spatial memory, failure to adapt to novel environments, and delayed noradrenaline (NA) recovery in the [...] Read more.
Retrotransposon Gag-like 4 (RTL4), a gene acquired from a retrovirus, is a causative gene in autism spectrum disorder. Its knockout mice exhibit increased impulsivity, impaired short-term spatial memory, failure to adapt to novel environments, and delayed noradrenaline (NA) recovery in the frontal cortex. However, due to its very low expression in the brain, it remains unknown which brain cells express RTL4 and its dynamics in relation to NA. We addressed these issues using knock-in mice carrying endogenous Rtl4 fused to Venus, which encodes a fluorescent protein. The RTL4-Venus fusion protein was detected as a secreted protein in the midbrain, hypothalamus, hippocampus and amygdala in the postnatal brain. Its signal intensity was high during critical periods of neonatal adaptation to novel environments. It was upregulated by various stimuli, including isoproterenol administration, whereas it was decreased by anesthesia but was maintained by milnacipran administration, suggesting its highly sensitive response to stressors, possible dependence on the arousal state and involvement in the NA reuptake process. In vitro mixed glial culture experiments demonstrated that Rtl4 is a microglial gene and suggested that RTL4 secretion responds rapidly to isoproterenol. Microglial RTL4 plays an important role in the NA response and possibly in the development of the NAergic neuronal network in the brain. Full article
(This article belongs to the Special Issue Molecular Research on Human Retrovirus Infection: 2nd Edition)
Show Figures

Figure 1

11 pages, 6658 KiB  
Article
Attempts to Create Transgenic Mice Carrying the Q3924E Mutation in RyR2 Ca2+ Binding Site
by Xiao-hua Zhang, Fu-lei Tang, Allison M. Trouten and Martin Morad
Cells 2024, 13(24), 2051; https://doi.org/10.3390/cells13242051 - 12 Dec 2024
Viewed by 941
Abstract
Over 200 point mutations in the ryanodine receptor (RyR2) of the cardiac sarcoplasmic reticulum (SR) are known to be associated with cardiac arrhythmia. We have already reported on the calcium signaling phenotype of a point mutation in RyR2 Ca2+ binding site Q3925E [...] Read more.
Over 200 point mutations in the ryanodine receptor (RyR2) of the cardiac sarcoplasmic reticulum (SR) are known to be associated with cardiac arrhythmia. We have already reported on the calcium signaling phenotype of a point mutation in RyR2 Ca2+ binding site Q3925E expressed in human stem-cell-derived cardiomyocytes (hiPSC-CMs) that was found to be lethal in a 9-year-old girl. CRISPR/Cas9-gene-edited mutant cardiomyocytes carrying the RyR2-Q3925E mutation exhibited a loss of calcium-induced calcium release (CICR) and caffeine-triggered calcium release but continued to beat arrhythmically without generating significant SR Ca2+ release, consistent with a remodeling of the calcium signaling pathway. An RNAseq heat map confirmed significant changes in calcium-associated genes, supporting the possibility of remodeling. To determine the in situ cardiac phenotype in an animal model of this mutation, we generated a knock-in mouse model of RyR2-Q3924E+/− using the CRISPR/Cas9 technique. We obtained three homozygous and one chimera mice, but they all died before reaching 3 weeks of age, preventing the establishment of germline mutation transmission in their offspring. A histo-pathological analysis of the heart showed significant cardiac hypertrophy, suggesting the Q3924E-RyR2 mutation was lethal to the mice. Full article
(This article belongs to the Special Issue Ca2+ Signaling and Calcium-Binding Proteins in Human Disease)
Show Figures

Graphical abstract

23 pages, 4076 KiB  
Article
Lipid Nanoparticles Enable Efficient In Vivo DNA Knock-In via HITI-Mediated Genome Editing
by Jun Hirose, Emi Aizawa, Shogo Yamamoto, Mingyao Xu, Shigenori Iwai and Keiichiro Suzuki
Biomolecules 2024, 14(12), 1558; https://doi.org/10.3390/biom14121558 - 6 Dec 2024
Viewed by 1662
Abstract
In vivo genome editing holds great therapeutic potential for treating monogenic diseases by enabling precise gene correction or addition. However, improving the efficiency of delivery systems remains a key challenge. In this study, we investigated the use of lipid nanoparticles (LNPs) for in [...] Read more.
In vivo genome editing holds great therapeutic potential for treating monogenic diseases by enabling precise gene correction or addition. However, improving the efficiency of delivery systems remains a key challenge. In this study, we investigated the use of lipid nanoparticles (LNPs) for in vivo knock-in of ectopic DNA. Our in vitro experiments demonstrated that the homology-independent targeted integration (HITI)-mediated genome-editing method achieved significantly higher knock-in efficiency at the Alb locus in hepatic cells compared to the traditional homology-directed repair (HDR)-mediated approach. By optimizing LNP composition and administration routes, we successfully achieved HITI-mediated GFP knock-in (2.1–2.7%) in the livers of mice through intravenous delivery of LNP-loaded genome editing components. Notably, repeated intravenous dosing led to a twofold increase in liver GFP knock-in efficiency (4.3–7.0%) compared to a single dose, highlighting the potential for cumulative genome editing effects. These findings provide a solid foundation for the use of LNPs in in vivo knock-in strategies, paving the way for future genome-editing therapies. Full article
Show Figures

Graphical abstract

19 pages, 16136 KiB  
Article
Chemogenetic Modulation of Preoptic Gabre Neurons Decreases Body Temperature and Heart Rate
by Ziyue Wang, Lanxiang Li, Miao Li, Zhonghua Lu, Lihua Qin, Robert Konrad Naumann and Hong Wang
Int. J. Mol. Sci. 2024, 25(23), 13061; https://doi.org/10.3390/ijms252313061 - 5 Dec 2024
Viewed by 1070
Abstract
The preoptic area of the hypothalamus is critical for regulation of brain–body interaction, including circuits that control vital signs such as body temperature and heart rate. The preoptic area contains approximately 70 molecularly distinct cell types. The Gabre gene is expressed in a [...] Read more.
The preoptic area of the hypothalamus is critical for regulation of brain–body interaction, including circuits that control vital signs such as body temperature and heart rate. The preoptic area contains approximately 70 molecularly distinct cell types. The Gabre gene is expressed in a subset of preoptic area cell types. It encodes the GABA receptor ε-subunit, which is thought to confer resistance to anesthetics at the molecular level, but the function of Gabre cells in the brain remains largely unknown. We generated and have extensively characterized a Gabre-cre knock-in mouse line and used chemogenetic tools to interrogate the function of Gabre cells in the preoptic area. Comparison with macaque GABRE expression revealed the conserved character of Gabre cells in the preoptic area. In awake mice, we found that chemogenetic activation of Gabre neurons in the preoptic area reduced body temperature, whereas chemogenetic inhibition had no effect. Furthermore, chemogenetic inhibition of Gabre neurons in the preoptic area decreased the heart rate, whereas chemogenetic activation had no effect under isoflurane anesthesia. These findings suggest an important role of preoptic Gabre neurons in maintaining vital signs such as body temperature and heart rate during wakefulness and under anesthesia. Full article
Show Figures

Figure 1

18 pages, 5632 KiB  
Article
Microglia-Impaired Phagocytosis Contributes to the Epileptogenesis in a Mouse Model of Dravet Syndrome
by I-Chun Chen, Shih-Yin Ho, Che-Wen Tsai, En-Li Chen and Horng-Huei Liou
Int. J. Mol. Sci. 2024, 25(23), 12721; https://doi.org/10.3390/ijms252312721 - 27 Nov 2024
Viewed by 1060
Abstract
Dravet syndrome (DS) is a genetic disorder caused by a deficit in the Nav1.1 channel, leading to drug-resistant epilepsy. The Nav1.1 channel plays a crucial role in microglial cell activation, and microglia are recognized as key mediators of seizures. In this study, we [...] Read more.
Dravet syndrome (DS) is a genetic disorder caused by a deficit in the Nav1.1 channel, leading to drug-resistant epilepsy. The Nav1.1 channel plays a crucial role in microglial cell activation, and microglia are recognized as key mediators of seizures. In this study, we explored the role of microglia in DS-related epileptogenesis using a knock-in mouse model (Scn1aE1099X/+) that mimics a subset of DS patients. In these DS mice, we observed a significant downregulation of the Nav1.1 channel in microglia. This channel deficit led microglia to adopt a pro-inflammatory state in their quiescent phase. In the LPS-activated state, microglia predominantly exhibited an intermediate morphology rather than the expected fully activated form. The reduced expression of pro-inflammatory cytokines was detected in microglia following treatment with LPS. Notably, we found a significant decrease in the phagocytic ability of microglia in DS mice. Electrophysiological studies revealed an increased immature synaptic activity in the dentate gyrus in DS mice. The impaired microglial phagocytosis of damaged cells, combined with reduced cytokine secretion, may result in an excess of immature synaptic connections, neuronal hyperexcitation, and the formation of abnormal neural circuits in the hippocampus of Scn1aE1099X/+ mice. These changes could potentially contribute to mechanisms relevant to epileptogenesis in DS. Full article
(This article belongs to the Section Molecular Neurobiology)
Show Figures

Figure 1

15 pages, 7039 KiB  
Article
Rectal Epithelial Stem Cell Kinetics in Acute Radiation Proctitis
by Sharmila Ghosh, Akinori Morita, Yuichi Nishiyama, Masahiro Sakaue, Ken Fujiwara, Daiki Morita, Yuichiro Sonoyama, Yuichi Higashi and Megumi Sasatani
Int. J. Mol. Sci. 2024, 25(20), 11252; https://doi.org/10.3390/ijms252011252 - 19 Oct 2024
Cited by 1 | Viewed by 1184
Abstract
The intestinal tract is a typical radiosensitive tissue, and radiation rectal injury is a severe side effect that limits the prescribed dose in radiotherapy of the abdominal and pelvic region. Understanding the post-irradiation kinetics of Lgr5-positive stem cells is crucial in comprehending [...] Read more.
The intestinal tract is a typical radiosensitive tissue, and radiation rectal injury is a severe side effect that limits the prescribed dose in radiotherapy of the abdominal and pelvic region. Understanding the post-irradiation kinetics of Lgr5-positive stem cells is crucial in comprehending this adverse process. In this study, we utilized Lgr5-EGFP knock-in mice expressing EGFP and LGR5 antibody fluorescence staining of wild-type mice. At the state of radiation injury, the qPCR analysis showed a significant decrease in the expression level of Lgr5 in the rectal epithelial tissue. The dose-response relationship analysis showed that at low to moderate doses up to 10 gray (Gy), Lgr5-clustered populations were observed at the base of the crypt, whereas at sublethal doses (20 Gy and 29 Gy), the cells exhibited a dot-like scatter pattern, termed Lgr5-dotted populations. During recovery, 30 days post-irradiation, Lgr5-clustered populations gradually re-emerged while Lgr5-dotted populations declined, implying that some of the Lgr5-dotted stem cell populations re-clustered, aiding regenerations. Based on statistical analysis of the dose-response relationship using wild-type mice, the threshold dose for destroying these stem cell structures is 18 Gy. These findings may help set doses in mouse abdominal irradiation experiments for radiation intestinal injury and for understanding the histological process of injury development. Full article
(This article belongs to the Special Issue Molecular Research of Gastrointestinal Disease 2.0)
Show Figures

Figure 1

32 pages, 8935 KiB  
Article
Cognitive Effects of Simulated Galactic Cosmic Radiation Are Mediated by ApoE Status, Sex, and Environment in APP Knock-In Mice
by Laura Wieg, Jason C. Ciola, Caroline C. Wasén, Fidelia Gaba, Brianna R. Colletti, Maren K. Schroeder, Robert G. Hinshaw, Millicent N. Ekwudo, David M. Holtzman, Takashi Saito, Hiroki Sasaguri, Takaomi C. Saido, Laura M. Cox and Cynthia A. Lemere
Int. J. Mol. Sci. 2024, 25(17), 9379; https://doi.org/10.3390/ijms25179379 - 29 Aug 2024
Viewed by 1636
Abstract
Cosmic radiation experienced during space travel may increase the risk of cognitive impairment. While simulated galactic cosmic radiation (GCRsim) has led to memory deficits in wildtype (WT) mice, it has not been investigated whether GCRsim in combination with genetic risk factors for Alzheimer’s [...] Read more.
Cosmic radiation experienced during space travel may increase the risk of cognitive impairment. While simulated galactic cosmic radiation (GCRsim) has led to memory deficits in wildtype (WT) mice, it has not been investigated whether GCRsim in combination with genetic risk factors for Alzheimer’s disease (AD) worsens memory further in aging mice. Here, we investigated the central nervous system (CNS) effects of 0 Gy (sham) or 0.75 Gy five-ion GCRsim or 2 Gy gamma radiation (IRR) in 14-month-old female and male APPNL-F/NL-F knock-in (KI) mice bearing humanized ApoE3 or ApoE4 (APP;E3F and APP;E4F). As travel to a specialized facility was required for irradiation, both traveled sham-irradiated C57BL/6J WT and KI mice and non-traveled (NT) KI mice acted as controls for potential effects of travel. Mice underwent four behavioral tests at 20 months of age and were euthanized for pathological and biochemical analyses 1 month later. Fecal samples were collected pre- and post-irradiation at four different time points. GCRsim seemed to impair memory in male APP;E3F mice compared to their sham counterparts. Travel tended to improve cognition in male APP;E3F mice and lowered total Aβ in female and male APP;E3F mice compared to their non-traveled counterparts. Sham-irradiated male APP;E4F mice accumulated more fibrillar amyloid than their APP;E3F counterparts. Radiation exposure had only modest effects on behavior and brain changes, but travel-, sex-, and genotype-specific effects were seen. Irradiated mice had immediate and long-term differences in their gut bacterial composition that correlated to Alzheimer’s disease phenotypes. Full article
(This article belongs to the Special Issue Advanced Science in Alzheimer’s Disease)
Show Figures

Figure 1

19 pages, 3115 KiB  
Article
Analytical Post-Embedding Immunogold–Electron Microscopy with Direct Gold-Labelled Monoclonal Primary Antibodies against RIBEYE A- and B-Domain Suggests a Refined Model of Synaptic Ribbon Assembly
by Stella Papadopoulos, René Tinschert, Iason Papadopoulos, Xenia Gerloff and Frank Schmitz
Int. J. Mol. Sci. 2024, 25(13), 7443; https://doi.org/10.3390/ijms25137443 - 6 Jul 2024
Viewed by 1640
Abstract
Synaptic ribbons are the eponymous specializations of continuously active ribbon synapses. They are primarily composed of the RIBEYE protein that consists of a unique amino-terminal A-domain and carboxy-terminal B-domain that is largely identical to the ubiquitously expressed transcriptional regulator protein CtBP2. Both RIBEYE [...] Read more.
Synaptic ribbons are the eponymous specializations of continuously active ribbon synapses. They are primarily composed of the RIBEYE protein that consists of a unique amino-terminal A-domain and carboxy-terminal B-domain that is largely identical to the ubiquitously expressed transcriptional regulator protein CtBP2. Both RIBEYE A-domain and RIBEYE B-domain are essential for the assembly of the synaptic ribbon, as shown by previous analyses of RIBEYE knockout and knockin mice and related investigations. How exactly the synaptic ribbon is assembled from RIBEYE subunits is not yet clear. To achieve further insights into the architecture of the synaptic ribbon, we performed analytical post-embedding immunogold–electron microscopy with direct gold-labelled primary antibodies against RIBEYE A-domain and RIBEYE B-domain for improved ultrastructural resolution. With direct gold-labelled monoclonal antibodies against RIBEYE A-domain and RIBEYE B-domain, we found that both domains show a very similar localization within the synaptic ribbon of mouse photoreceptor synapses, with no obvious differential gradient between the centre and surface of the synaptic ribbon. These data favour a model of the architecture of the synaptic ribbon in which the RIBEYE A-domain and RIBEYE B-domain are located similar distances from the midline of the synaptic ribbon. Full article
(This article belongs to the Collection Feature Papers in Molecular Neurobiology)
Show Figures

Figure 1

15 pages, 3254 KiB  
Article
Effects of Dietary Protein Intake Levels on Peripheral Circadian Rhythm in Mice
by Yerim Han, Jinyoung Shon, So Young Kwon and Yoon Jung Park
Int. J. Mol. Sci. 2024, 25(13), 7373; https://doi.org/10.3390/ijms25137373 - 5 Jul 2024
Cited by 1 | Viewed by 1664
Abstract
The regulation of the circadian clock plays an important role in influencing physiological conditions. While it is reported that the timing and quantity of energy intake impact circadian regulation, the underlying mechanisms remain unclear. This study investigated the impact of dietary protein intake [...] Read more.
The regulation of the circadian clock plays an important role in influencing physiological conditions. While it is reported that the timing and quantity of energy intake impact circadian regulation, the underlying mechanisms remain unclear. This study investigated the impact of dietary protein intake on peripheral clocks. Firstly, transcriptomic analysis was conducted to investigate molecular targets of low-protein intake. Secondly, mPer2::Luc knock-in mice, fed with either a low-protein, normal, or high-protein diet for 6 weeks, were analyzed for the oscillation of PER2 expression in peripheral tissues and for the expression profiles of circadian and metabolic genes. Lastly, the candidate pathway identified by the in vivo analysis was validated using AML12 cells. As a result, using transcriptomic analysis, we found that the low-protein diet hardly altered the circadian rhythm in the central clock. In animal experiments, expression levels and period lengths of PER2 were different in peripheral tissues depending on dietary protein intake; moreover, mRNA levels of clock-controlled genes and endoplasmic reticulum (ER) stress genes were affected by dietary protein intake. Induction of ER stress in AML12 cells caused an increased amplitude of Clock and Bmal1 and an advanced peak phase of Per2. This result shows that the intake of different dietary protein ratios causes an alteration of the circadian rhythm, especially in the peripheral clock of mice. Dietary protein intake modifies the oscillation of ER stress genes, which may play key roles in the regulation of the circadian clock. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
Show Figures

Figure 1

Back to TopTop