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Gene Knockout Mice (gene + knockout_mouse)
Selected AbstractsIncreased neurogenesis and brain-derived neurotrophic factor in neurokinin-1 receptor gene knockout miceEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2003Sara Morcuende Abstract It has previously been shown that chronic treatment with antidepressant drugs increases neurogenesis and levels of brain-derived neurotrophic factor in the hippocampus. These changes have been correlated with changes in learning and long-term potentiation and may contribute to the therapeutic efficacy of antidepressant drug treatment. Recently, antagonists at the neurokinin-1 receptor, the preferred receptor for the neuropeptide substance P, have been shown to have antidepressant activity. Mice with disruption of the neurokinin-1 receptor gene are remarkably similar both behaviourally and neurochemically to mice maintained chronically on antidepressant drugs. We demonstrate here that there is a significant elevation of neurogenesis but not cell survival in the hippocampus of neurokinin-1 receptor knockout mice. Neurogenesis can be increased in wild-type but not neurokinin-1 receptor knockout mice by chronic treatment with antidepressant drugs which preferentially target noradrenergic and serotonergic pathways. Hippocampal levels of brain-derived neurotrophic factor are also two-fold higher in neurokinin-1 receptor knockout mice, whereas cortical levels are similar. Finally, we examined hippocampus-dependent learning and memory but found no clear enhancement in neurokinin-1 receptor knockout mice. These data argue against a simple correlation between increased levels of neurogenesis or brain-derived neurotrophic factor and mnemonic processes in the absence of increased cell survival. They support the hypothesis that increased neurogenesis, perhaps accompanied by higher levels of brain-derived neurotrophic factor, may contribute to the efficacy of antidepressant drug therapy. [source] Inhibition of scratching behaviour caused by contact dermatitis in histidine decarboxylase gene knockout miceEXPERIMENTAL DERMATOLOGY, Issue 3 2005M. Seike Abstract:, A neuronal system dedicated to itch consists of primary afferent and spinothalamic projection neurons. Histamine is thought to be one of the main mediators for the transmission of itch sensation. However, there are little available information on the role of histamine in scratching behaviour and sensory transmission of atopic dermatitis and chronic eczema. In the present study, the role of histamine in scratching behaviour and neural conduction of sensation in the chronic eczema model was investigated by using l-histidine decarboxylase (HDC) gene knockout mice lacking histamine. The chronic contact dermatitis was induced with daily application of diphenylcyclopropenone (DCP) on a hind paw of HDC (+/+) and HDC (,/,) mice for 2 months. The observation of scratching behaviour and the hot-plate test were performed in both mice. Histological studies were performed in the skin and spinal cord tissues. Histological examination revealed that both HDC (+/+) and HDC (,/,) mice displayed the similar extent of inflammatory cell infiltration, hyperplastic epidermis and newly spreading of neuronal processes in the skin tissue. Scratching behaviour was exclusively induced in HDC (+/+) mice, whereas it was barely observed in HDC (,/,) mice. The expression of c-Fos was specifically upregulated in HDC (+/+) mice in lamina I of the spinal dorsal horn following repeated DCP application. Scratching behaviour in chronic contact dermatitis in mice was thought mainly mediated with histamine. The afferent pathway of sensation in chronic contact dermatitis model may connect with the central nervous system through lamina I of the spinal dorsal horn. [source] Oxytocin and estrogen receptor , and , knockout mice provide discriminably different odor cues in behavioral assaysGENES, BRAIN AND BEHAVIOR, Issue 4 2004M. Kavaliers Social behavior involves both the recognition and production of social cues. Mice with selective deletion (knockout) of either the gene for oxytocin (OT) or genes for the estrogen receptor (ER) -, or -, display impaired social recognition. In this study we demonstrate that these gene knockout mice also provide discriminably different social stimuli in behavioral assays. In an odor choice test, which is a measure of social interest and discrimination, outbred female Swiss-Webster mice discriminated the urine odors of male knockouts (KO: OTKO, ,ERKO, ,ERKO) from the odors of their wildtype littermates (WT: OTWT, ,ERWT, ,ERWT). Females showed marked initial choices of the urine odors of OTWT and ,ERWT males over those of OTKO and ,ERKO males, and ,ERKO males over ,ERWT males. The odors of OTKO and ,ERKO males also induced aversive, analgesic responses, with the odors of WTs having no significant effects. Odors of both the ,ERWT and ,ERKO males induced aversive, analgesic responses, with the odors of the WT inducing significantly greater analgesia. The odors of restraint stressed WT and KO males also elicited analgesia with, again, females displaying significantly greater responses to the odors of stressed OTKO and ,ERKO males than their WTs, and significantly lower analgesia to the odors of stressed ,ERKO than ,ERWT males. These findings show that the KO mice are discriminated from their WTs on the basis of odor and that the various KOs differ in the relative attractiveness/aversiveness of their odors. Therefore, in behavioral assays one causal route by which gene inactivation alters the social behavior of knockout mice may be mediated through the partners' modified responses to their odors. [source] Dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell,specific signal transducer and activator of transcription 3 gene knockout mice,HEPATOLOGY, Issue 5 2010Norio Horiguchi Liver injury is associated with inflammation, which is generally believed to accelerate the progression of liver diseases; however, clinical data show that inflammation does not always correlate with hepatocelluar damage in some patients. Investigating the cellular mechanisms underlying these events using an experimental animal model, we show that inflammation may attenuate liver necrosis induced by carbon tetrachloride (CCl4) in myeloid-specific signal transducer and activator of transcription 3 (STAT3) knockout mice. As an important anti-inflammatory signal, conditional deletion of STAT3 in myeloid cells results in markedly enhanced liver inflammation after CCl4 injection. However, these effects are also accompanied by reduced liver necrosis, correlating with elevated serum interleukin-6 (IL-6) and hepatic STAT3 activation. An additional deletion of STAT3 in hepatocytes in myeloid-specific STAT3 knockout mice restored hepatic necrosis but decreased liver inflammation. Conclusion: Inflammation-mediated STAT3 activation attenuates hepatocellular injury induced by CCl4 in myeloid-specific STAT3 knockout mice, suggesting that inflammation associated with a predominance of hepatoprotective cytokines that activate hepatic STAT3 may reduce rather than accelerate hepatocellular damage in patients with chronic liver diseases. Hepatology 2010 [source] Role of Inducible Nitric Oxide Synthase in Skeletal Adaptation to Acute Increases in Mechanical Loading,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2002Makoto Watanuki M.D. Abstract To clarify the role of nitric oxide (NO) in regulation of bone metabolism in response to skeletal loading, we examined inducible NO synthase (iNOS) gene knockout mice in the tail-suspension model. Histomorphometric analyses of proximal tibias revealed that 7 days of tail suspension decreased the bone volume (BV/TV) and bone formation rate (BFR/BS) and increased the osteoclast surface (Oc.S/BS) in mice with all iNOS genotypes. Both iNOS+/+ and iNOS+/, mice responded to subsequent 14-day reloading, with increases in BV/TV and BFR/BS and a decrease in Oc.S/BS, whereas these responses were abolished in iNOS,/, mice. The osteoblasts flattened after tail suspension appeared cuboidal during subsequent reloading. Immunoreactivity for iNOS was detected in these osteoblasts and osteocytes by immunohistochemistry. These defective responses after reloading were rescued in iNOS,/, mice by treatment with an NO donor nitroglycerine (NG). Conversely, the responses in iNOS+/+ mice were inhibited by treatment with an NOS inhibitor aminoguanidine (AG). In bone marrow cell cultures, mineralized nodules derived from iNOS,/, mice after reloading were significantly reduced. Taken together, our results suggest that NO generated by iNOS in osteoblasts plays a critical role in adjusting bone turnover and increasing osteogenic activity in response to the acute increase in mechanical loading after tail suspension. [source] Increased methamphetamine-induced locomotor activity and behavioral sensitization in histamine-deficient miceJOURNAL OF NEUROCHEMISTRY, Issue 4 2002Yasuhiko Kubota Abstract We have recently suggested that the brain histamine has an inhibitory role on the behavioral effects of methamphetamine by pharmacological studies. In this study, we used the histidine decarboxylase gene knockout mice and measured the spontaneous locomotor activity, the changes of locomotion by single and repeated administrations of methamphetamine, and the contents of brain monoamines and amino acids at 1 h after a single administration of methamphetamine. In the histidine decarboxylase gene knockout mice, spontaneous locomotor activity during the dark period was significantly lower than in the wild-type mice. Interestingly, methamphetamine-induced locomotor hyperactivity and behavioral sensitization were facilitated more in the histidine decarboxylase gene knockout mice. In the neurochemical study, noradrenaline and O -phosphoserine were decreased in the midbrain of the saline-treated histidine decarboxylase gene knockout mice. On the other hand, single administration of methamphetamine decreased GABA content of the midbrain of the wild-type mice, but did not alter that of histidine decarboxylase gene knockout mice. These results suggest that the histamine neuron system plays a role as an awakening amine in concert with the noradrenaline neuron system, whereas it has an inhibitory role on the behavioral effects of methamphetamine through the interaction with the GABAergic neuron system. [source] Do multidrug resistance-associated protein-1 and -2 play any role in the elimination of estradiol-17,-glucuronide and 2,4-dinitrophenyl- S -glutathione across the blood,cerebrospinal fluid barrier?JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2004Young-Joo Lee Abstract The purpose of this study was to examine the role of multidrug resistance-associated protein-1 and -2 (Mrp1 and Mrp2) in the efflux transport of organic anions across the blood,cerebrospinal fluid (CSF) barrier. The CSF concentration of estradiol-17,-glucuronide (E217,G) and 2,4-dinitrophenyl- S -glutathione (DNP-SG) in the CSF after intracerebroventricular and intravenous injection were compared between wild-type and Mrp1 gene knockout mice. There was no significant difference in the apparent CSF elimination rate constants of E217,G (0.158 and 0.145 min,1) and DNP-SG (0.116 and 0.0779 min,1) between wild-type and Mrp1 knockout mice, respectively. After intravenous administration of E217,G, its brain-to-serum and CSF-to-serum concentration ratios in Mrp1 knockout mice were not significantly different from those in the wild-type. Results from in vivo and in vitro studies using Eisai hyperbilirubinemic rats, in which Mrp2 is hereditarily deficient, were similar to those using normal rats. Quantitative polymerase chain reaction (PCR) showed that the expression level of Mrp4 and Mrp5 was several times higher than that of Mrp1, whereas the expression levels of Mrp2, Mrp3, and Mrp6 were negligible or low. Therefore, Mrp4 and Mrp5 may contribute to the efflux transport of E217,G and DNP- SG from the CSF. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:99,107, 2004 [source] GABAA -Receptor , Subunit Knockout Mice Have Multiple Defects in Behavioral Responses to EthanolALCOHOLISM, Issue 12 2001Robert M. Mihalek Background: The ,-aminobutyric acid type A receptors (GABARs) are involved in mediating some of the behavioral effects of beverage alcohol (ethanol). However, the unique pharmacological and behavioral responses conferred by each of the various receptor subunits are not well understood. Methods: To address the role of the GABAR , subunit in mediating ethanol responses, gene knockout mice that lack this subunit were tested for a variety of ethanol-induced behavioral responses. Results: Our results indicate that, compared with controls, ,-deficient mice (,,/,) have (1) reduced ethanol consumption, (2) attenuated withdrawal from chronic ethanol exposure, and (3) reduced anticonvulsant (seizure-protective) effects of ethanol. These mice demonstrate a normal anxiolytic response to ethanol and a normal hypothermic response to ethanol, and they develop both chronic and acute tolerance. Conclusions: These results further establish the link between GABARs and specific behavioral responses to ethanol and begin to reveal the role of the , subunit in these responses. [source] Familial fibronectin glomerulopathy: analysis of chromosome 1q32 and uteroglobin gene loci in a large New Zealand familyNEPHROLOGY, Issue 5 2001Robert Walker SUMMARY: Recently, a newly recognized familial glomerulopathy with predominant fibronectin deposits has been reported. This is the first report of a family with this condition in Australasia and spans two generations over a 30-year period, with the histologically confirmed glomerulopathy present in the father and five out of eight siblings. The clinical presentations have ranged from asymptomatic proteinuria, pregnancy-associated proteinuria and the nephrotic syndrome to hypertension and proteinuria with progressive renal failure. The time-course from presentation to renal failure was over a 20 years. Histology demonstrated global and diffuse thickening of capillary loops, but no cellular proliferation. Immunofluorescence demonstrated granular positivity for IgM in the capillary loops only. Electron microscopy demonstrated massive electron-dense subendothelial granular deposits with occasional small fibrils and unremarkable epithelial cell foot processes. Immunohistochemical staining was strongly positive for fibronectin and negative for type I or type IV collagen and transforming growth factor , in all biopsies. Genetic studies of familial fibronectin glomerulopathy have recently highlighted two genetic loci. Firstly, a large five-generation pedigree has been described with linkage of fibronectin glomerulopathy to chromosome 1q32. Secondly, fibronectin glomerulopathy has been reported in uteroglobin gene knockout mice. In our studies, DNA sequence analysis of the uteroglobin gene showed that it was normal in all family members, and a DNA polymorphism in the uteroglobin gene did not co-segregate with the disease. In addition, DNA microsatellite markers at the 1q32 locus did not co-segregate with the disease in our family. We presume that the underlying abnormality involves as yet undefined glomerular extracellular matrix regulation and is inherited as an autosomal dominant condition. These data favour genetic heterogeneity for the aetiology of fibronectin glomerulopathy. [source] Regulation of IgE-receptor expression, IgE occupancy and secretory capacity of mast cellsAPMIS, Issue 10 2000XIAO-JUN Chen Mast cells play an important role in initiating and modulating allergic and inflammatory reactions. Their responsiveness is determined by three important factors: the expression of IgE receptors on the cell surface, the IgE occupancy of these receptors, and the intrinsic secretory capacity of the cells. In this review, we will summarise some findings relevant to these three aspects of mast cell function, and discuss possible regulatory mechanisms. It appears that the genetic background as well as environmental factors influence all three of these components of the response. T cells appear to play an important role in regulating the IgE-receptor expression and also, independently, the intrinsic secretory capacity of mast cells via an unidentified route, possibly involving the secretory signal transduction chain directly. IgE itself appears to have an important role in the regulation of IgE-receptor expression, as indicated by the upregulation of receptors in vitro in the presence of IgE, and the absence of IgE-binding capacity of mast cells in IL-4 gene knockout mice, lacking IgE production. The IgE-receptors of mast cells are saturated to a high degree under different normal conditions, without an obvious relation to antigenic stimulation, also in athymic animals. We have suggested that this basal IgE content on mast cells may be the result of an antigen-independent production of IgE directed by the mast cells themselves and serving regulatory purposes, modifying the secretory response and preventing a massive possibly harmful degranulation. [source] DNA repair dysfunction in gastrointestinal tract cancersCANCER SCIENCE, Issue 3 2008Yoshihiko Maehara The DNA repair system surveys the genome, which is always suffering from exposure to both exogenous as well as endogenous mutagens, to maintain the genetic information. The fact that the basis of this DNA repair system is highly conserved, from prokaryote to mammalian cells, suggests the importance of precise genome maintenance mechanisms for organisms. In the past 15 years, considerable progress has been made in understanding how repair processes interact and how disruptions of these mechanisms lead to the accumulation of mutations and carcinogenesis. In 1993, two groups reported that DNA mismatch repair could be associated with hereditary non-polyposis colorectal cancer, indicating a connection between faulty DNA repair function and cancer. More recently, an inherited disorder of DNA glycosylase, which removes mutagenic oxidized base from DNA, has been reported in individuals with a predisposition to multiple colorectal adenomas and carcinomas. This is the first report that directly indicates the role of the repair of oxidative DNA in human inherited cancer. Studies from gene knockout mice have elucidated the principal role of these repair systems in the process of carcinogenesis. Moreover, clinical samples derived from cancer patients have shown the direct involvement. This review focuses on the function of DNA mismatch repair and oxidative DNA/nucleotide repair among various DNA repair systems in cells, both of which are essentially involved in the carcinogenesis of gastrointestinal tract cancer. (Cancer Sci 2008; 99: 451,458) [source] Gene trap mutagenesis in mice: New perspectives and tools in cancer researchCANCER SCIENCE, Issue 1 2008Ken-ichi Yamamura The complete human DNA sequence of the human genome was published in 2004 and we entered the postgenomic era. However, many studies showed that gene function is much more complex than we expected, and that mutation of disease genes does not give any clue for molecular mechanisms for disease development. Since the first report on gene knockout mice in 1989, knockout mice have been shown to be a powerful tool for functional genomics and for the dissection of developmental processes in human diseases. In accordance with this successful application of knockout mice, three major mouse knockout programs are now underway worldwide, to mutate all protein-encoding genes in mouse embryonic stem cells using a combination of gene trapping and gene targeting. We developed the exchangeable gene trap method suitable for large scale mutagenesis in mice. In this method we can produce null mutation and post-insertional modification, enabling replacement of the marker gene with a gene of interest and conditional knockout. We herein discuss the effect of this gene-driven type approach for cancer research, especially for finding the genes that are related to cancer, but are paid little attention in hypothesis-driven cancer research. (Cancer Sci 2008; 99: 1,6) [source] Enhanced Formation of Azoxymethane-induced Colorectal Adenocarcinoma in ,, T Lymphocyte-deficient MiceCANCER SCIENCE, Issue 8 2001Shunji Matsuda T cell receptor (TCR) ,, -positive T lymphocytes, which are localized mostly within the intraepithe-lial space of intestinal epithelium, have been suggested to play a role in maintaining the normal configuration of intestinal epithelium. However, the role of TCR,, -positive T lymphocytes in the formation and progression of colorectal adenocarcinoma that originates from colorectal epithelial cells remains to be elucidated. In this study, TCR,, and TCR,, -positive T lymphocyte-deficient mice (homozygous TCR, and TCR,-gene knockout mice) and the background wild-type mice were administered azoxymethane, and the formation of macroscopic tumors and microscopic aberrant crypt foci in colorectal mucosa were compared among the three types of mice. Well-differentiated adenocarcinoma appeared 5 months after 5 administrations of azoxymethane (10 mg/kg weight) only in a few TCR,-gene knockout mice and the frequency of the carcinoma-bearing mice was increased at 7 and 9 months after the administration. Aberrant crypt foci were also detected in the colorectal mucosa of TCR,-gene knockout mice to a greater extent than in colorectal mucosa of TCR,-gene knockout mice 1 month after the azoxymethane administration. These results suggest that TCR,, -positive T lymphocytes, which are present mainly in the intraepithelial space, play a role in suppression of the formation and progression of colorectal adenocarcinoma in mice. [source] | |||||||||||||