NF-kappaB activity in transgenic mice: developmental regulation and tissue specificity

Development ◽  
1996 ◽  
Vol 122 (7) ◽  
pp. 2117-2128 ◽  
Author(s):  
R. Schmidt-Ullrich ◽  
S. Memet ◽  
A. Lilienbaum ◽  
J. Feuillard ◽  
M. Raphael ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Early Development ◽  
Developmental Regulation ◽  
Mouse Development ◽  
Knock Out ◽  
Cellular Genes ◽  
Development And Differentiation ◽  
The Central Nervous System ◽  
Nf Kappab ◽  
Knock Out Mice

The transcription factor family NF-kappaB/Rel is responsible for the regulation of a large number of cellular genes and some viruses. Since there is a strong similarity between the NF-kappaB/Rel family members and the Drosophila melanogaster protein DORSAL, which is activated early during embryogenesis, we were interested in determining the pattern of NF-kappaB activity during mouse development. Two lacZ reporter constructs, each driven by promoter elements that are dependent on the presence of nuclear NF-kappaB/Rel activity, were used to produce transgenic mice. The analysis of these mice did not identify nuclear NF-kappaB/Rel activity in early development prior to implantation or during the gastrulation processes. Earliest expression of the lacZ transgene was detected on day E12.5. Before birth lacZ expression was seen in discrete regions of the rhombencephalon of the developing brain, in the spinal medulla, in some of the blood vessels and in the thymus. After birth, the NF-kappaB/Rel activity in the thymus remained but nuclear activity was also found in the bone marrow, in the spleen and in the capsule of the lymph nodes. In the central nervous system, drastic changes in NF-kappaB/Rel activity could be observed in the first 3 weeks after birth, when the cortex and the cerebellum reach functional and morphological maturity. Considering the results of the p50, p65, relB and c-rel knock-out mice and our present findings, we believe that the NF-kappaB/Rel proteins known so far are probably not implicated in processes of early development and differentiation of the different tissues, but rather in maintaining their function once matured.

scholarly journals Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xin Ding ◽  
Jin Wang ◽  
Miaoxin Huang ◽  
Zhangpeng Chen ◽  
Jing Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Knock Out ◽  
Classical Complement Pathway ◽  
Synaptic Remodeling ◽  
The Central Nervous System ◽  
System Activation ◽  
Knock Out Mice ◽  
Synaptic Pruning

AbstractMicroglia play a key role in regulating synaptic remodeling in the central nervous system. Activation of classical complement pathway promotes microglia-mediated synaptic pruning during development and disease. CD47 protects synapses from excessive pruning during development, implicating microglial SIRPα, a CD47 receptor, in synaptic remodeling. However, the role of microglial SIRPα in synaptic pruning in disease remains unclear. Here, using conditional knock-out mice, we show that microglia-specific deletion of SIRPα results in decreased synaptic density. In human tissue, we observe that microglial SIRPα expression declines alongside the progression of Alzheimer’s disease. To investigate the role of SIRPα in neurodegeneration, we modulate the expression of microglial SIRPα in mouse models of Alzheimer’s disease. Loss of microglial SIRPα results in increased synaptic loss mediated by microglia engulfment and enhanced cognitive impairment. Together, these results suggest that microglial SIRPα regulates synaptic pruning in neurodegeneration.

scholarly journals Deletion of Kif5c Does Not Alter Prion Disease Tempo or Spread in Mouse Brain

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1391
Author(s):  
Brent Race ◽  
Katie Williams ◽  
Chase Baune ◽  
James F. Striebel ◽  
Clayton W. Winkler ◽  
...  
Keyword(s):  
Prion Disease ◽  
Molecular Motors ◽  
Prion Diseases ◽  
Mouse Strains ◽  
Survival Times ◽  
Knock Out ◽  
Transport Vesicles ◽  
The Central Nervous System ◽  
Knock Out Mice ◽  
Scrapie Strains

In prion diseases, the spread of infectious prions (PrPSc) is thought to occur within nerves and across synapses of the central nervous system (CNS). However, the mechanisms by which PrPSc moves within axons and across nerve synapses remain undetermined. Molecular motors, including kinesins and dyneins, transport many types of intracellular cargo. Kinesin-1C (KIF5C) has been shown to transport vesicles carrying the normal prion protein (PrPC) within axons, but whether KIF5C is involved in PrPSc axonal transport is unknown. The current study tested whether stereotactic inoculation in the striatum of KIF5C knock-out mice (Kif5c−/−) with 0.5 µL volumes of mouse-adapted scrapie strains 22 L or ME7 would result in an altered rate of prion spreading and/or disease timing. Groups of mice injected with each strain were euthanized at either pre-clinical time points or following the development of prion disease. Immunohistochemistry for PrP was performed on brain sections and PrPSc distribution and tempo of spread were compared between mouse strains. In these experiments, no differences in PrPSc spread, distribution or survival times were observed between C57BL/6 and Kif5c−/− mice.

scholarly journals EBI2 Is Temporarily Upregulated in MO3.13 Oligodendrocytes during Maturation and Regulates Remyelination in the Organotypic Cerebellar Slice Model

2021 ◽  
Vol 22 (9) ◽  
pp. 4342
Author(s):  
Maria Velasco-Estevez ◽  
Nina Koch ◽  
Ilona Klejbor ◽  
Stephane Laurent ◽  
Kumlesh K. Dev ◽  
...  
Keyword(s):  
Human Brain ◽  
Immune Cells ◽  
White Matter Lesions ◽  
Demyelinating Diseases ◽  
Cellular Migration ◽  
Knock Out ◽  
New Information ◽  
Chemically Induced ◽  
The Central Nervous System ◽  
Knock Out Mice

The EBI2 receptor regulates the immune system and is expressed in various immune cells including B and T lymphocytes. It is also expressed in astrocytes in the central nervous system (CNS) where it regulates pro-inflammatory cytokine release, cell migration and protects from chemically induced demyelination. Its signaling and expression are implicated in various diseases including multiple sclerosis, where its expression is increased in infiltrating immune cells in the white matter lesions. Here, for the first time, the EBI2 protein in the CNS cells in the human brain was examined. The function of the receptor in MO3.13 oligodendrocytes, as well as its role in remyelination in organotypic cerebellar slices, were investigated. Human brain sections were co-stained for EBI2 receptor and various markers of CNS-specific cells and the human oligodendrocyte cell line MO3.13 was used to investigate changes in EBI2 expression and cellular migration. Organotypic cerebellar slices prepared from wild-type and cholesterol 25-hydroxylase knock-out mice were used to study remyelination following lysophosphatidylcholine (LPC)-induced demyelination. The data showed that EBI2 receptor is present in OPCs but not in myelinating oligodendrocytes in the human brain and that EBI2 expression is temporarily upregulated in maturing MO3.13 oligodendrocytes. Moreover, we show that migration of MO3.13 cells is directly regulated by EBI2 and that its signaling is necessary for remyelination in cerebellar slices post-LPC-induced demyelination. The work reported here provides new information on the expression and role of EBI2 in oligodendrocytes and myelination and provides new tools for modulation of oligodendrocyte biology and therapeutic approaches for demyelinating diseases.

scholarly journals Notch1 control of oligodendrocyte differentiation in the spinal cord

2002 ◽  
Vol 158 (4) ◽  
pp. 709-718 ◽  
Author(s):  
Stéphane Genoud ◽  
Corinna Lappe-Siefke ◽  
Sandra Goebbels ◽  
Freddy Radtke ◽  
Michel Aguet ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Transgenic Mice ◽  
Oligodendrocyte Differentiation ◽  
Temporal Regulation ◽  
Development And Differentiation ◽  
The Central Nervous System

We have selectively inhibited Notch1 signaling in oligodendrocyte precursors (OPCs) using the Cre/loxP system in transgenic mice to investigate the role of Notch1 in oligodendrocyte (OL) development and differentiation. Early development of OPCs appeared normal in the spinal cord. However, at embryonic day 17.5, premature OL differentiation was observed and ectopic immature OLs were present in the gray matter. At birth, OL apoptosis was strongly increased in Notch1 mutant animals. Premature OL differentiation was also observed in the cerebrum, indicating that Notch1 is required for the correct spatial and temporal regulation of OL differentiation in various regions of the central nervous system. These findings establish a widespread function of Notch1 in the late steps of mammalian OPC development in vivo.

Expression of HbC and HbS, but not HbA, results in activation of K-Cl cotransport activity in transgenic mouse red cells

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2384-2390 ◽  
Author(s):  
Jose R. Romero ◽  
Sandra M. Suzuka ◽  
Ronald L. Nagel ◽  
Mary E. Fabry
Keyword(s):  
Transgenic Mice ◽  
Hemoglobin Concentration ◽  
Red Cells ◽  
Mean Corpuscular Hemoglobin ◽  
Red Cell ◽  
Knock Out ◽  
High K ◽  
Hb S ◽  
Knock Out Mice ◽  
Human Red Cells

Abstract Elevation of K-Cl cotransport in patients with homozygous hemoglobin (Hb) S or HbC increases red cell mean corpuscular hemoglobin concentration (MCHC) and contributes significantly to pathology. Elucidation of the origin of elevated K-Cl cotransport in red cells with mutant hemoglobins has been confounded by the concomitant presence of reticulocytes with high K-Cl cotransport. In red cells of control mice (C57BL), transgenic mice that express only human HbA, and transgenic mice that express both mouse globins and human HbS, volume stimulation is weak and insensitive to NO3- and dihydroindenyl-oxy-alkanoic acid (DIOA). DIOA and NO3- are inhibitors in all other mammalian red cells. In contrast, in knock-out mice expressing exclusively human hemoglobin HbC or HbS+γ, replacement of isotonic Cl- media by hypotonic Cl- resulted in strong volume stimulation and sensitivity to DIOA, okadaic acid, and NO3-. In summary, we find that HbC, under all conditions, and HbS+γ, in the absence of mouse globins, have significant quantitative and qualitative effects on K-Cl cotransport in mouse red cells and activate mouse K-Cl. We conclude that human globins are able to stimulate the activity and/or regulation of K-Cl cotransport in mouse red cells. These observations support the contention that HbS and HbC stimulate K-Cl cotransport in human red cells.

Abstract 267: Preserved Cardiac Contractility and Venous Return in Beta-arrestin2 Transgenic Mice During Sepsis With Insufficient Resuscitation

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Hui Yan ◽  
James Denney ◽  
Hui Li ◽  
Christopher Daniels ◽  
Krishna Singh ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cardiac Contractility ◽  
Cecal Ligation ◽  
Hemodynamic Instability ◽  
Negative Regulator ◽  
Experimental Sepsis ◽  
Knock Out ◽  
Function Regulator ◽  
Knock Out Mice ◽  
Protective Signaling

β-arrestin 2 is a negative regulator of inflammation and a protective signaling transducer in acute heart injury. In this study, using echocardiography and Millar Pressure-Volume systems, we found that heart dysfunction accompanied with hemodynamic instability occurred rapidly after experimental sepsis with insufficient resuscitation in wild type and β-arrestin 2 knock out mice but not in β-arrestin 2 transgenic mice. β-arrestin 2 overexpression is associated with preserved preload, cardiac output, systolic contractility and diastolic elasticity after cecal ligation and puncture (CLP). Furthermore, β-arrestin 2 overexpression up-regulated IL-6/IL-6R/gp130/STAT3 anti-apoptotic signaling through suppressing p38 activation and subsequently inhibiting phosphorylation of membrane bound gp130, the signal transducer part of IL-6 receptor complex. In conclusion, β-arrestin 2 is a crucial cardiac function regulator in sepsis.

scholarly journals Interferon regulatory factor-2 drives megakaryocytic differentiation

2004 ◽  
Vol 377 (2) ◽  
pp. 367-378 ◽  
Author(s):  
Emilia STELLACCI ◽  
Ugo TESTA ◽  
Eleonora PETRUCCI ◽  
Eleonora BENEDETTI ◽  
Roberto ORSATTI ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Growth Regulation ◽  
Fas Ligand ◽  
Regulation Of Transcription ◽  
Histone H4 ◽  
Differentiation Markers ◽  
Knock Out ◽  
Megakaryocytic Differentiation ◽  
Development And Differentiation ◽  
Knock Out Mice

IRFs [IFN (interferon) regulatory factors] constitute a family of transcription factors involved in IFN signalling and in the development and differentiation of the immune system. IRF-2 has generally been described as an antagonist of IRF-1-mediated transcription of IFN and IFN-inducible genes; however, it has been recently identified as a transcriptional activator of some genes, such as those encoding histone H4, VCAM-1 (vascular cell adhesion molecule-1) and Fas ligand. Biologically, IRF-2 plays an important role in cell growth regulation and has been shown to be a potential oncogene. Studies in knock-out mice have also implicated IRF-2 in the differentiation and functionality of haematopoietic cells. Here we show that IRF-2 expression in a myeloid progenitor cell line leads to reprogramming of these cells towards the megakaryocytic lineage and enables them to respond to thrombopoietin, as assessed by cell morphology and expression of specific differentiation markers. Up-regulation of transcription factors involved in the development of the megakaryocytic lineage, such as GATA-1, GATA-2, FOG-1 (friend of GATA-1) and NF-E2 (nuclear factor-erythroid-2), and transcriptional stimulation of the thrombopoietin receptor were also demonstrated. Our results provide evidence for a key role for IRF-2 in the induction of a programme of megakaryocytic differentiation, and reveal a remarkable functional diversity of this transcription factor in the regulation of cellular responses.

Transgenic mice studies demonstrate a role for platelet factor 4 in thrombosis: dissociation between anticoagulant and antithrombotic effect of heparin

Blood ◽  
2004 ◽  
Vol 104 (10) ◽  
pp. 3173-3180 ◽  
Author(s):  
Don E. Eslin ◽  
Chunyan Zhang ◽  
Kathleen J. Samuels ◽  
Lubica Rauova ◽  
Li Zhai ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Thrombus Formation ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Knock Out ◽  
Thrombosis Model ◽  
Knock Out Mice ◽  
Positively Charged

Abstract The platelet-specific chemokine platelet factor 4 (PF4) is released in large amounts at sites of vascular injury. PF4 binds to heparin with high affinity, but its in vivo biologic role has not been defined. We studied the role of PF4 in thrombosis using heterozygote and homozygote PF4 knock-out mice (mPF4+/– and mPF4–/–, respectively) and transgenic mice overexpressing human PF4 (hPF4+). None of these lines had an overt bleeding diathesis, but in a FeCl3 carotid artery thrombosis model, all showed impaired thrombus formation. This defect in thrombus formation in the mPF4–/– animals was corrected by infusing hPF4 over a narrow concentration range. The thrombotic defect in the mPF4+/– and mPF4–/– animals was particularly sensitive to infusions of the negatively charged anticoagulant heparin. However, the same amount of heparin paradoxically normalized thrombus formation in the hPF4+ animals, although these animals were anticoagulated systemically. Upon infusion of the positively charged protein, protamine sulfate, the reverse was observed with mPF4+/– and mPF4–/– animals having improved thrombosis, with the hPF4+ animals having worsened thrombus formation. These studies support an important role for PF4 in thrombosis, and show that neutralization of PF4 is an important component of heparin's anticoagulant effect. The mechanisms underlying these observations of PF4 biology and their clinical implications remain to be determined.

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