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  • EXPRESSION  (5)
  • MOUSE  (3)
  • 1
    Keywords: brain ; EXPRESSION ; MODEL ; MODELS ; SYSTEM ; COHORT ; GENE ; PROTEIN ; transcription ; DRUG ; MICE ; RESPONSES ; MECHANISM ; TRANSCRIPTION FACTOR ; RATS ; mechanisms ; BINDING ; ALPHA ; CREB ; ELEMENT ; ELEMENT-BINDING PROTEIN ; ISOFORM ; MUTANT ; NERVOUS-SYSTEM ; NO ; TARGETED MUTATION ; DECREASE ; STRESS ; MUTATION ; MODULATION ; REGION ; REGIONS ; Jun ; INVOLVEMENT ; BEHAVIOR ; FOOD ; LACKING ; BINDING PROTEIN ; molecular ; BINDING-PROTEIN ; MOLECULAR-MECHANISM ; DEPENDENCE ; NEURONS ; KNOCKOUT MICE ; ADDICTION ; CERULEUS ; conditioned place preference ; emotional behavior ; locus coeruleus ; LOCUS-COERULEUS NEURONS ; MOLECULAR-MECHANISMS ; NEURAL PLASTICITY ; opiate addiction ; OPIATE-WITHDRAWAL
    Abstract: The transcription factor cAMP-responsive element binding protein (CREB) has been shown to regulate different physiological responses including drug addiction and emotional behavior. Molecular changes including adaptive modifications of the transcription factor CREB are produced during drug dependence in many regions of the brain, including the locus coeruleus (LC), but the molecular mechanisms involving CREB within these regions have remained controversial. To further investigate the involvement of CREB in emotional behavior, drug reward and opioid physical dependence, we used two independently generated CREB-deficient mice. We employed the Cre/loxP system to generate mice with a conditional CREB mutation restricted to the nervous system, where all CREB isoforms are lacking in the brain (Creb / (NesCre)). A genetically defined cohort of the previously described hypomorphic Creb / (alphaDelta) mice, in which the two major transcriptionally active isoforms (alpha and Delta) are disrupted throughout the organism, were also used. First, we investigated the responses to stress of the CREB-deficient mice in several paradigms, and we found an increased anxiogenic-like response in the both Creb / mutant mice in different behavioral models. We investigated the rewarding properties of drugs of abuse (cocaine and morphine) and natural reward (food) using the conditioned place-preference paradigm. No modification of motivational responses of morphine, cocaine, or food was observed in mutant mice. Finally, we evaluated opioid dependence by measuring the behavioral expression of morphine withdrawal and electrophysiological recordings of LC neurons. We showed an important attenuation of the behavioral expression of abstinence and a decrease in the hyperactivity of LC neurons in both Creb / mutant mice. Our results emphasize the selective role played by neuronal CREB in emotional-like behavior and the somatic expression morphine withdrawal, without participating in the rewarding properties induced by morphine and cocaine
    Type of Publication: Journal article published
    PubMed ID: 15029152
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  • 2
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; IRRADIATION ; proliferation ; SURVIVAL ; CELL ; COMBINATION ; IN-VIVO ; VIVO ; GENERATION ; PROTEIN ; PROTEINS ; transcription ; MICE ; ACTIVATION ; DNA ; TRANSCRIPTION FACTOR ; ANTIGEN ; T cell ; T cells ; T-CELL ; T-CELLS ; BINDING ; PHOSPHORYLATION ; CELL-SURVIVAL ; ELEMENT ; ELEMENT-BINDING PROTEIN ; knockout ; MUTANT ; NO ; TRANSCRIPTION FACTORS ; TRANSGENIC MICE ; PROMOTER ; transgenic ; RESPONSIVE ELEMENT ; T lymphocyte ; OVEREXPRESSION ; rodent ; T lymphocytes ; BINDING PROTEIN ; thymus ; BINDING-PROTEIN ; IL-2 PRODUCTION ; MOLECULAR-BASIS
    Abstract: Recent generation of genetically modified Creb1 mutant mice has revealed an important role for CREB (CAMP responsive element binding protein) and the related proteins CREM (CAMP responsive element modulator) and ATF1 (activating transcription factor 1) in cell survival, in agreement with previous studies using overexpression of dominant-negative CREB (dnCREB). CREB and ATF1 are abundantly expressed in T cells and are rapidly activated by phosphorylation when T cells are stimulated through the T cell antigen receptor. We show that T cell-specific loss of CREB in mice, in combination with the loss of ATF1, results in reduced thymic cellularity and delayed thymic recovery following sublethal irradiation but no changes in T cell development or activation. These data show that loss of CREB function has specific effects on thymic T lymphocyte proliferation and homeostasis in vivo
    Type of Publication: Journal article published
    PubMed ID: 15214044
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  • 3
    Keywords: CELLS ; EXPRESSION ; MOUSE-BRAIN ; TRANSGENIC MICE ; CRE ; KeyWords Plus: SITE-SPECIFIC RECOMBINATION
    Abstract: We describe the generation of transgenic mouse lines expressing the Cre recombinase enzyme in brain under control of the CamKIIalpha gene present in a BAC expression vector. The CamKIIalpha BAC transgene gave a faithful expression pattern resembling the pattern of the endogenous CamKIIalpha gene. Specifically, high levels of CamKIIalpha Cre were detected in hippocampus, cortex, and amygdala, and lower levels were detected in striatum, thalamus, and hypothalamus. As expected, no expression was detected in the cerebellum or outside of the brain. The expression level of the BAC CamKIIalpha driven Cre was shown to be copy number dependent. To test the activity of the Cre recombinase, the transgenic mice were crossed with mice harbouring the CREB (cAMP response element binding protein) allele with the 10th exon flanked by two loxP sites, and recombination was monitored by the disappearance of the CREB protein. Finally, evaluation of the developmental postnatal expression of the CamKIIalpha Cre BAC revealed the expression of the Cre recombinase as early as P3.
    Type of Publication: Journal article published
    PubMed ID: 11668676
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  • 4
    Keywords: brain ; Germany ; LONG-TERM ; GENE ; PROTEIN ; transcription ; TRANSCRIPTION FACTOR ; REDUCTION ; WATER ; MEMORY ; FORM ; CAMP ; CELL-SURVIVAL ; conditioned taste aversion ; CONDITIONED TASTE-AVERSION ; CREB ; DEFICITS ; DELETION ; ELEMENT ; ELEMENT-BINDING PROTEIN ; ELEMENT-BINDING-PROTEIN ; fear conditioning ; hippocampus ; ISOFORM ; ISOFORMS ; knockout ; LATE-PHASE ; learning ; LONG-TERM POTENTIATION ; LTD ; LTP ; MAP KINASE ; MOUSE ; MOUSE-BRAIN ; MUTANT ; NERVOUS-SYSTEM ; NO ; PERFORMANCE ; PROBE ; RESPONSE ELEMENT ; score ; STAGE ; synaptic plasticity ; TARGETED MUTATION ; TRANSCRIPTION FACTORS ; TRANSGENIC MICE ; TRIAL ; TRIALS ; WATER MAZE
    Abstract: Previous studies addressing the role of the transcription factor cAMP response element-binding protein (CREB) in mammalian long-term synaptic plasticity and memory by gene targeting were compromised by incomplete deletion of the CREB isoforms. Therefore, we generated conditional knock-out strains with a marked reduction or complete deletion of all CREB isoforms in the hippocampus. In these strains, no deficits could be detected in lasting forms of hippocampal long-term potentiation (LTP) and long-term depression (LTD). When tested for hippocampus-dependent learning, mutants showed normal context-dependent fear conditioning. Water maze learning was impaired during the early stages, but many mutants showed satisfactory scores in probe trials thought to measure hippocampus-dependent spatial memory. However, conditioned taste aversion learning, a putatively hippocampus-independent memory test, was markedly impaired. Our data indicate that in the adult mouse brain, loss of CREB neither prevents learning nor substantially affects performance in some hippocampus-dependent tasks. Furthermore, it spares LTP and LTD in paradigms that are sensitive enough to detect deficits in other mutants. This implies either a species-specific or regionally restricted role of CREB in the brain and/or a compensatory upregulation of the cAMP response element modulator (CREM) and other as yet unidentified transcription factors
    Type of Publication: Journal article published
    PubMed ID: 12867515
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  • 5
    Keywords: brain ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; MODEL ; VITRO ; SYSTEM ; NEW-YORK ; GENE ; GENOME ; PROTEIN ; recombination ; ALPHA ; MOUSE ; PROMOTER ; PROMOTERS ; inactivation ; BETA ; alpha complementation,iCre recombinase,IoxP ; COMPLEMENTATION ; POLYPEPTIDE ; SITE-SPECIFIC RECOMBINATION
    Abstract: The Cre-IoxP system is increasingly exploited for spatial and temporal gene inactivation. Here we present a novel approach to achieve this goal of selective gene inactivation. Following the model of complementation in the beta-galactosidase enzyme, where the enzyme is split into independent polypeptides which are able to associate and maintain the enzymatic activity, we divided the Cre recombinase into two independent polypeptides (one containing the NH2 terminus (alpha) and a second one containing the COOH-terminus (beta)). Individually, the two polypeptides have no detectable activity. However, when coexpressed the polypeptides are able to associate, giving rise to Cre enzymatic activity, which optimally is as high as 30% of that seen with wildtype Cre recombinase in vitro. We present this strategy as a modification of the traditional Cre-IoxP system, which could be used to obtain a highly specific recombination pattern by expressing the two halves under the control of separate promoters. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 14502574
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  • 6
    Keywords: brain ; PEPTIDE ; RECEPTOR ; CELLS ; EXPRESSION ; GROWTH ; INHIBITOR ; BLOOD ; CELL ; GENE ; GENES ; PROTEIN ; transcription ; METABOLISM ; MICE ; RELEASE ; ACTIVATION ; TRANSCRIPTION FACTOR ; IMPACT ; hepatocytes ; BINDING ; PHOSPHORYLATION ; SIGNAL ; ACID ; CREB ; ELEMENT-BINDING PROTEIN ; TRANSGENIC MICE ; hormone ; DISRUPTION ; BODY ; MUTANT MICE ; HYPOPLASIA ; BINDING PROTEIN ; LOSSES ; SIGNALS ; EXPANSION ; CAMP RESPONSE ELEMENT ; CREB FUNCTION ; HORMONE-RELEASING-HORMONE ; NEURAL STEM
    Abstract: The principal regulation of body growth is via a cascade of hormone signals emanating from the hypothalamus, by release of GHRH, which then directs the somatotroph cells of the pituitary to release GH into the blood stream. This in turn leads to activation of signal transducer and activator of transcription 5-dependent expression of genes such as IGF-1 in hepatocytes, acid labile substance, and serine protease inhibitor 2.1, resulting in body growth. Here, using conditional cAMP response element binding protein ( CREB) mutant mice, we show that loss of the CREB transcription factor in the brain, but not the pituitary, results in reduced postnatal growth consistent with dwarfism caused by GH deficiency. We demonstrate that although there appears to be no significant impact upon the expression of GHRH mRNA in CREB mutant mice, the amount of GHRH peptide is reduced. These findings show that CREB is required for the efficient production of GHRH in hypothalamus, in addition to its previously reported role in pituitary GH production and somatotroph expansion
    Type of Publication: Journal article published
    PubMed ID: 16141355
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  • 7
    Keywords: brain ; GENE ; GENOME ; MOUSE ; TRANSGENIC MICE ; SITE-SPECIFIC RECOMBINATION ; STEM-CELLS ; CRE RECOMBINASE ; SOMATIC MUTAGENESIS
    Abstract: Here we describe the generation of a new tamoxifen-inducible double Cre fusion protein generated by fusing two ERT2 domains onto both ends of the iCre recombinase (a codon improved Cre recombinase). This Cre fusion protein (ERiCreER) had a twofold increased activity in cell culture assays than the previously described MerCreMer Cre double fusion protein. ERiCreER was targeted to the brain by placing it under the control of the promoter from the CamKIIalpha gene using a 170 kb BAC. The fusion protein was detected in hippocampus, cortex, striatum, thalamus, and hypothalamus but not in cerebellum. The ERiCreER was cytoplasmatic in the absence of tamoxifen and translocated into the nucleus upon tamoxifen administration. The activity of the ERiCreER was tested in vivo by mating the CamKIIalpha ERiCreER transgenic line with mice harbouring exon 10 of the CREB gene flanked by two LoxP sites. In the absence of tamoxifen, no background activity was detected in mice older than 6 months. After tamoxifen administration, most if not all of the ERiCreER fusion protein translocated from the cytoplasm to the nucleus; however, only 5-10% of the "floxed" CREB allele was recombined. Recombination was also visualised at the cellular level by following the upregulation of the CREM protein, which corresponds precisely with CREB loss/recombination. Unlike in other tissues (Sohal et al., 2001; Tannour-Louet et al., 2002), it appears that in brain, although ERiCreER can bind tamoxifen, the Cre-recombinase cannot be fully activated.
    Type of Publication: Journal article published
    PubMed ID: 12395386
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