In vivo role of caspases in excitotoxic neuronal death: generation and analysis of transgenic mice expressing baculoviral caspase inhibitor, p35, in postnatal neurons

2002 ◽  
Vol 108 (1-2) ◽  
pp. 18-32 ◽  
Author(s):  
Masanori Tomioka ◽  
Keiro Shirotani ◽  
Nobuhisa Iwata ◽  
Hahn-Jun Lee ◽  
Fusheng Yang ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Neuronal Death ◽  
Caspase Inhibitor ◽  
Excitotoxic Neuronal Death

scholarly journals Oocyte-Specific Overexpression of Mouse Bone Morphogenetic Protein-15 Leads to Accelerated Folliculogenesis and an Early Onset of Acyclicity in Transgenic Mice

Endocrinology ◽  
2008 ◽  
Vol 149 (6) ◽  
pp. 2807-2815 ◽  
Author(s):  
Heather E. McMahon ◽  
Osamu Hashimoto ◽  
Pamela L. Mellon ◽  
Shunichi Shimasaki
Keyword(s):  
Transgenic Mice ◽  
Bone Morphogenetic Protein ◽  
Early Onset ◽  
Ovarian Function ◽  
Chimeric Protein ◽  
Mature Protein ◽  
Follicle Growth ◽  
Morphogenetic Protein

Whereas mutations in the bmp15 gene cause infertility in ewes and women due to defects in folliculogenesis, most defects in female mice lacking bone morphogenetic protein (BMP)-15 are confined to the ovulation process, supportive of the observation that functional mouse BMP-15 is barely detected in oocytes in vivo until after the LH surge. In addition, the mouse BMP-15 proprotein is not processed into the functional mature protein in transfected cells. However, a chimeric protein consisting of the human proregion, human cleavage site, and mouse mature region (termed hhmBMP-15) is processed and the mature protein secreted. To study the role of BMP-15 in folliculogenesis, we generated transgenic mice overexpressing hhmBMP-15, exclusively in oocytes during folliculogenesis and confirmed the overexpression of mouse BMP-15 mature protein. Immature transgenic mice exhibited accelerated follicle growth with decreased primary follicles and an increase in secondary follicles. Granulosa cells of immature mice displayed an increased mitotic index and decreased FSH receptor mRNA expression. Adult mice had normal litter sizes but an increased number of atretic antral follicles. Interestingly, aging mice exhibited an early onset of acyclicity marked by increased diestrus length and early occurrence of constant diestrus. These findings indicate the role of BMP-15 in vivo in promoting follicle growth and preventing follicle maturation, resulting in an early decline in the ovarian reserve of transgenic mice. Therefore, the lack of mouse BMP-15 during early folliculogenesis in the wild-type mice may be relevant to their polyovulatory nature as well as the preservation of ovarian function as the mice age.

scholarly journals Role of c-Fos in orthodontic tooth movement: an in vivo study using transgenic mice

2020 ◽  
Author(s):  
Maximilian G. Decker ◽  
Cita Nottmeier ◽  
Julia Luther ◽  
Anke Baranowsky ◽  
Bärbel Kahl-Nieke ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Tooth Movement ◽  
Orthodontic Tooth Movement ◽  
In Vivo Study

scholarly journals Nrf Transcription Factors in Keratinocytes Are Essential for Skin Tumor Prevention but Not for Wound Healing

2006 ◽  
Vol 26 (10) ◽  
pp. 3773-3784 ◽  
Author(s):  
Ulrich auf dem Keller ◽  
Marcel Huber ◽  
Tobias A. Beyer ◽  
Angelika Kümin ◽  
Christina Siemes ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transgenic Mice ◽  
Wound Repair ◽  
Target Genes ◽  
Dominant Negative ◽  
Skin Tumor ◽  
Cellular Stress Response ◽  
Skin Development

ABSTRACT The Nrf2 transcription factor is a key player in the cellular stress response through its regulation of cytoprotective genes. In this study we determined the role of Nrf2-mediated gene expression in keratinocytes for skin development, wound repair, and skin carcinogenesis. To overcome compensation by the related Nrf1 and Nrf3 proteins, we expressed a dominant-negative Nrf2 mutant (dnNrf2) in the epidermis of transgenic mice. The functionality of the transgene product was verified in vivo using mice doubly transgenic for dnNrf2 and an Nrf2-responsive reporter gene. Surprisingly, no abnormalities of the epidermis were observed in dnNrf2-transgenic mice, and even full-thickness skin wounds healed normally. However, the onset, incidence, and multiplicity of chemically induced skin papillomas were strikingly enhanced, whereas the progression to squamous cell carcinomas was unaltered. We provide evidence that the enhanced tumorigenesis results from reduced basal expression of cytoprotective Nrf target genes, leading to accumulation of oxidative damage and reduced carcinogen detoxification. Our results reveal a crucial role of Nrf-mediated gene expression in keratinocytes in the prevention of skin tumors and suggest that activation of Nrf2 in keratinocytes is a promising strategy to prevent carcinogenesis of this highly exposed organ.

scholarly journals NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death Both In Vitro and In Vivo

2007 ◽  
Vol 27 (11) ◽  
pp. 2846-2857 ◽  
Author(s):  
Y. Liu ◽  
T. P. Wong ◽  
M. Aarts ◽  
A. Rooyakkers ◽  
L. Liu ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Neuronal Death ◽  
Nmda Receptor Subunits ◽  
Excitotoxic Neuronal Death

scholarly journals Insight Into the Emerging Role of Striatal Neurotransmitters in the Pathophysiology of Parkinson’s Disease and Huntington’s Disease: A Review

2019 ◽  
Vol 17 (2) ◽  
pp. 165-175 ◽  
Author(s):  
Sumit Jamwal ◽  
Puneet Kumar
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Basal Ganglia ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Death ◽  
Critical Role ◽  
Altered Level ◽  
Excitotoxic Neuronal Death

Alteration in neurotransmitters signaling in basal ganglia has been consistently shown to significantly contribute to the pathophysiological basis of Parkinson’s disease and Huntington’s disease. Dopamine is an important neurotransmitter which plays a critical role in coordinated body movements. Alteration in the level of brain dopamine and receptor radically contributes to irregular movements, glutamate mediated excitotoxic neuronal death and further leads to imbalance in the levels of other neurotransmitters viz. GABA, adenosine, acetylcholine and endocannabinoids. This review is based upon the data from clinical and preclinical studies to characterize the role of various striatal neurotransmitters in the pathogenesis of Parkinson’s disease and Huntington’s disease. Further, we have collected data of altered level of various neurotransmitters and their metabolites and receptor density in basal ganglia region. Although the exact mechanisms underlying neuropathology of movement disorders are not fully understood, but several mechanisms related to neurotransmitters alteration, excitotoxic neuronal death, oxidative stress, mitochondrial dysfunction, neuroinflammation are being put forward. Restoring neurotransmitters level and downstream signaling has been considered to be beneficial in the treatment of Parkinson’s disease and Huntington’s disease. Therefore, there is an urgent need to identify more specific drugs and drug targets that can restore the altered neurotransmitters level in brain and prevent/delay neurodegeneration.

MiR-221 and MiR-222 Patterns Characterize Burkitt Lymphoma in Human and Mouse Model

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1304-1304
Author(s):  
Jessica Consiglio ◽  
Andrea Vecchione ◽  
Marco Galasso ◽  
Alberto Rocci ◽  
Mario Acunzo ◽  
...  
Keyword(s):  
B Cells ◽  
Mouse Model ◽  
Transgenic Mice ◽  
Lymph Nodes ◽  
Mirna Expression ◽  
Burkitt Lymphoma ◽  
Noncoding Rnas ◽  
Down Regulation

Abstract Abstract 1304 Recently, a class of noncoding RNAs called microRNA (miRNAs) has emerged as critical gene regulators in cell growth, differentiation, disease and development. MiRNAs are 18–24 nucleotide long noncoding RNAs, which regulate gene expression by pairing with 3′ untranslated region (UTR) of target mRNA and inhibiting protein translation and/or inducing mRNA degradation. Deregulated miRNA expression is reported in various human diseases including lymphomas, suggesting an important role in their pathogenesis. According to WHO classification, Burkitt lymphoma (BL) is a rare, highly aggressive NHL composed of monomorphic medium-sized B cells with multiple nucleoli and numerous mitotic figures and is more common in children than in adults. The molecular feature of BL is the translocation that places MYC under the control of immunoglobulin gene regulatory elements. High levels of c-MYC have been clearly shown to have a tumour-promoting effect. However, there is recent evidence that infrequent cases may lack an identifiable MYC translocation, the explanation for which is still uncertain, though suggesting the existence of pathogenetic mechanisms alternative to genetic alterations. Over the past years miRNA signatures have been described to characterize and classify different types of BL or to investigate the expression of miRNAs possibly regulated by c-Myc in BL cases positive or negative for Myc translocation. However, it remained unclear the functional role of differentially expressed miRNAs and no further studies have been conducted. We performed miRNA expression profile to gain further insights into the molecular pathology of BL. We conducted array analysis on a set of 5 sporadic BL patients, 3 endemic BL patients, 9 reactive tissues and 11 cases of mononucleosis. Our profile is the first one that shows the different expression between BL cases and normal B cells whereas recent miRNA profiles have been conducted in BL compared to other B-NHL (B-CLL, MCL & FL). A common trend of miRNAs altered expression was also observed by NanoString analysis in 10 BL cell lines compared to 5 normal CD-19+ B cells. Among several miRNAs previously described be deregulated in BL we identified a severe down-regulation of miR-221, miR-222 in all classes of comparisons we analyzed. The down-regulation of miR-221 and miR-222 associated to BL has been also confirmed by q-RT-PCR method in a different cohort of BL patients (20) compared to the healthy controls (6). We found that interesting considering the up-regulation of miR-221 and miR-222 previously confirmed in a lot of solid tumors by multiple studies. We are investigating a different role of the cluster miR-222 and miR-221 in lymphomas that have a different process in carcinogenesis than solid tumors. In vivo models to study the lymphomagenesis of BL have been created but until now no one studied the importance of the miRNAs in vivo. We analyzed the expression of miR-221 and miR-222 in a Myc transgenic mouse model. The transgene construct consists of the Myc oncogene (c-myc) in association with the Emu immunoglobulin heavy chain enhancer and Myc promoter. Expression of the mouse Myc transgene is restricted to the B cell lineage. Previously it has been shown an increase of pre-B cells in the bone marrow throughout life of hemizygotes and a transient increase in large pre-B cells in the blood at 3–4 weeks of age; moreover spontaneous pre-B and B cell lymphomas reach an incidence of 50% at 15–20 weeks in hemizygous progeny of a wildtype female mated with a hemizygous male. We observed the development of Burkitt lymphoma within 10 weeks of birth in 14 out of 25 Eu-Myc transgenic mice and a premature death in 5 out or 25 transgenic mice within 6–8 weeks of birth without showing any enlarged lymph nodes. Transgenic mice with masses showed the same phenotype characterized by enlarged spleen (3 fold), lymphosarcomas associated with BL and enlarged lymph nodes around the neck area. B-cells have been negatively selected from enlarged lymph nodes and enlarged spleen. A qRT-PCR has been conducted to evaluate the miR-221 and miR-222 expression. The miRNA levels showed a down-regulation in B cells collected from the masses when compared to normal B cells derived from the spleen of WT mice. In conclusion, our study reveals new insights into the functional significance in loss of miR-221 and miR-222 expression in BL pathogenesis. Disclosures: No relevant conflicts of interest to declare.

Klotho ablation converts the biochemical and skeletal alterations in FGF23 (R176Q) transgenic mice to a Klotho-deficient phenotype

2009 ◽  
Vol 296 (1) ◽  
pp. E79-E88 ◽  
Author(s):  
Xiuying Bai ◽  
Qiu Dinghong ◽  
Dengshun Miao ◽  
David Goltzman ◽  
Andrew C. Karaplis
Keyword(s):  
Transgenic Mice ◽  
Cortical Bone ◽  
Related Factor ◽  
Signaling Mechanism ◽  
Dihydroxyvitamin D ◽  
Hypomorphic Allele ◽  
Calcium Phosphorus

Transgenic mice overexpressing fibroblast growth factor (FGF23) (R176Q) ( F Tg) exhibit biochemical {hypophosphatemia, phosphaturia, abnormal 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] metabolism} and skeletal (rickets and osteomalacia) abnormalities attributable to FGF23 action. In vitro studies now implicate the aging-related factor Klotho in the signaling mechanism of FGF23. In this study, we used a mouse genetic approach to validate in vivo the pivotal role of Klotho in the metabolic and skeletal derangements associated with FGF23 (R176Q) overexpression. To this end, we crossed mice heterozygous for the hypomorphic Klotho allele ( Kl+/−) to F Tg mice and obtained F Tg transgenic mice homozygous for the Kl-hypomorphic allele ( F Tg/ Kl−/−). Mice were killed on postnatal day 50, and serum and tissues were procured for analysis and comparison with F Tg, wild-type, and Kl−/− controls. From 4 wk onward, F Tg/ Kl−/− mice were clearly distinguishable from F Tg mice and exhibited a striking phenotypic resemblance to the Kl−/− controls. Serum analysis for calcium, phosphorus, parathyroid hormone, 1,25(OH)2D3, and alkaline phosphatase activity confirmed the biochemical similarity between the F Tg/ Kl−/− and Kl−/− mice and their distinctness from the F Tg controls. The characteristic skeletal changes associated with FGF23 (R176Q) overexpression were also dramatically reversed by the absence of Klotho. Hence the wide, unmineralized growth plates and the osteomalacic abnormalities apparent in trabecular and cortical bone were completely reversed in the F Tg/ Kl−/− mice. Nevertheless, independent actions of Klotho on bone were suggested as manifested by alterations in mineralized bone, and in cortical bone volume which were observed in both the Kl−/− and F Tr/ Kl−/− mutants. In summary, our findings substantiate in vivo the essential role of Klotho in the mechanism of action of FGF23 in view of the fact that Klotho ablation converts the biochemical and skeletal manifestations resulting from FGF23 overexpression to a phenotype consistent with Klotho deficiency.

scholarly journals Critical Role of Egr Transcription Factors in Regulating Insulin Biosynthesis, Blood Glucose Homeostasis, and Islet Size

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3040-3053 ◽  
Author(s):  
Isabelle Müller ◽  
Oliver G. Rössler ◽  
Christine Wittig ◽  
Michael D. Menger ◽  
Gerald Thiel
Keyword(s):  
Transcription Factors ◽  
Glucose Tolerance ◽  
Transgenic Mice ◽  
Glucose Homeostasis ◽  
Insulin Biosynthesis ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Islet Size

Expression of early growth response protein (Egr)-1, a protein of the Egr family of zinc finger transcription factors, is stimulated in glucose-treated pancreatic β-cells and insulinoma cells. The purpose of this study was to elucidate the role of Egr transcription factors in pancreatic β-cells in vivo. To overcome the problem associated with redundancy of functions between Egr proteins, conditional transgenic mice were generated expressing a dominant-negative mutant of Egr-1 in pancreatic β-cells. The Egr-1 mutant interferes with DNA binding of all Egr proteins and thus impairs the biological functions of the entire Egr family. Expression of the Egr-1 mutant reduced expression of TGFβ and basic fibroblast growth factor, known target genes of Egr-1, whereas the expression of Egr-1, Egr-3, Ets-like gene-1 (Elk-1), and specificity protein-3 was not changed in the presence of the Egr-1 mutant. Expression of the homeobox protein pancreas duodenum homeobox-1, a major regulator of insulin biosynthesis, was reduced in islets expressing the Egr-1 mutant. Accordingly, insulin mRNA and protein levels were reduced by 75 or 25%, respectively, whereas expression of glucagon and somatostatin was not altered after expression of the Egr-1 mutant in β-cells. Glucose tolerance tests revealed that transgenic mice expressing the Egr-1 mutant in pancreatic β-cells displayed impaired glucose tolerance. In addition, increased caspase-3/7 activity was detected as a result of transgene expression, leading to a 20% decrease of the size of the islets. These results show that Egr proteins play an important role in controlling insulin biosynthesis, glucose homeostasis, and islet size of pancreatic β-cells in vivo.

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