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1.
Aunapuu M Roosaar P Järveots T Kurrikoff K Kõks S Vasar E Arend A 《Transgenic research》2008,17(6):1079-1089
Although cholecystokinin is a regulatory peptide with a predominant role in the brain and the gastrointestinal tract, there
is an increasing evidence for its role in the kidney. The aim of this study was to reveal morphological changes in the structure
of kidney of mice with cholecystokinin overexpression by means of light, transmission and scanning electron microscope, and
atomic force microscopy. Using immunohistochemistry the expression of important basement membrane proteins collagen IV, laminin
and fibronectin, as well the distribution of cholecystokinin-8 in the renal structures was evaluated. The altered morphology
of kidneys of mice with cholecystokinin overexpression was seen by all microscopic techniques used. The renal corpuscles were
relatively small with narrow capsular lumen. The basement membranes of renal tubules were thickened and the epithelial cells
were damaged, which was more pronounced for distal tubules. Characteristic feature was the increased number of vesicles seen
throughout the epithelial cells of proximal and especially in distal tubules reflecting to the enhanced cellular degeneration.
The relative expression of laminin but not collagen IV in the glomerular basement membrane was higher than in the tubular
basement membranes. The content of fibronectin, in opposite, was higher in tubular membranes. Cholecystokinin-8 was clearly
expressed in the glomeruli, in Bowman’s capsule, in proximal and distal tubules, and in collecting ducts. Ultrastructural
studies showed irregularly thickened glomerular basement membranes to which elongated cytopodia of differently shaped podocytes
were attached. As foot processes were often fused the number of filtration pores was decreased. In conclusion, cholecystokinin
plays important role in renal structural formation and in functioning as different aspects of urine production in mice with
cholecystokinin overexpression are affected-the uneven glomerular basement membrane thickening, structural changes in podocytes
and in filtration slits affect glomerular filtration, while damaged tubular epithelial cells and changed composition of thickened
tubular basement membranes affect reabsorption. 相似文献
2.
Altered morphology in transgenic tobacco plants that overproduce cytokinins in specific tissues and organs. 总被引:32,自引:0,他引:32
An auxin-inducible bidirectional promoter from the soybean SAUR gene locus was fused to a reporter gene in one direction and a cytokinin biosynthetic gene in the opposite direction and the expression of these fused genes was examined in transgenic tobacco. The Escherichia coli uidA gene, which encodes the enzyme beta-glucuronidase (GUS), was used as the reporter gene and the Agrobacterium tumefaciens ipt gene, which encodes the enzyme isopentenyl transferase, was used as the cytokinin biosynthetic gene. These constructs allowed the overproduction of cytokinins in tobacco in a tissue- and organ-specific manner. Localized overproduction of cytokinins was monitored using the GUS reporter gene and measured by an ELISA assay. The tissue- and organ-specific overproduction of cytokinins produced a number of morphological and physiological changes, including stunting, loss of apical dominance, reduction in root initiation and growth, either acceleration or prolonged delayed senescence in leaves depending on the growth conditions, adventitious shoot formation from unwounded leaf veins and petioles, altered nutrient distribution, and abnormal tissue development in stems. While some of these morphological changes result directly from the localized overproduction of cytokinins, other changes probably result from the mobilization of plant nutrients to tissues rich in cytokinins. 相似文献
3.
Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice 总被引:10,自引:0,他引:10
Alzheimer's disease is characterized by amyloid beta-peptide deposition, synapse loss, and neuronal death, which are correlated with cognitive impairments. Mutations in the presenilin-1 gene on chromosome 14 are causally linked to many cases of early-onset inherited Alzheimer's disease. We report that synaptosomes prepared from transgenic mice harboring presenilin-1 mutations exhibit enhanced elevations of cytoplasmic calcium levels following exposure to depolarizing agents, amyloid beta-peptide, and a mitochondrial toxin compared with synaptosomes from nontransgenic mice and mice overexpressing wild-type presenilin-1. Mitochondrial dysfunction and caspase activation following exposures to amyloid beta-peptide and metabolic insults were exacerbated in synaptosomes from presenilin-1 mutant mice. Agents that buffer cytoplasmic calcium or that prevent calcium release from the endoplasmic reticulum protected synaptosomes against the adverse effect of presenilin-1 mutations on mitochondrial function. Abnormal synaptic calcium homeostasis and mitochondrial dysfunction may contribute to the pathogenic mechanism of presenilin-1 mutations. 相似文献
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Miller et al. (this issue of Neuron) report that deletion of the 3'UTR of alpha-CaMKII mRNA prevents dendritic delivery of the mRNA in transgenic mice and thus local synthesis of alpha-CaMKII protein in dendrites. 3'UTR mutant mice exhibit decreases in alpha-CaMKII protein in postsynaptic densities, and deficits in late phase LTP and in memory consolidation. 相似文献
6.
Amyloid suppresses induction of genes critical for memory consolidation in APP + PS1 transgenic mice
Dickey CA Gordon MN Mason JE Wilson NJ Diamond DM Guzowski JF Morgan D 《Journal of neurochemistry》2004,88(2):434-442
Mice transgenic for mutated forms of the amyloid precursor protein (APP) plus presenilin-1 (PS1) genes (APP + PS1 mice) gradually develop memory deficits which correlate with the extent of amyloid deposition. The expression of several immediate-early genes (IEGs: Arc, Nur77 and Zif268) and several other plasticity-related genes (GluR1, CaMKIIalpha and Na-K- ATPase alphaIII) critical for learning and memory was normal in young APP + PS1 mice preceding amyloid deposition, but declined as mice grew older and amyloid deposits accumulated. Gene repression was less in APP + PS1 mouse brain regions that contain less Abeta and in APP mice compared with APP + PS1 mice, further linking the extent of amyloid deposition and the extent of gene repression. Critically, we demonstrated that amyloid deposition led specifically to impaired induction of the IEGs with no effects on basal expression using exposure to a novel environment 30 min prior to being killed to induce IEGs. These data imply that Abeta deposition can selectively reduce expression of multiple genes linked to synaptic plasticity, and provide a molecular basis for memory deficiencies found in transgenic APP mice and, most likely, in early stage Alzheimer's disease (AD). Presumably, pharmacological agents blocking the Abeta-related inhibition of gene expression will have benefit in AD. 相似文献
7.
Neuronal apoptosis and reversible motor deficit in dominant-negative GSK-3 conditional transgenic mice 总被引:2,自引:0,他引:2
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Gómez-Sintes R Hernández F Bortolozzi A Artigas F Avila J Zaratin P Gotteland JP Lucas JJ 《The EMBO journal》2007,26(11):2743-2754
Increased glycogen synthase kinase-3 (GSK-3) activity is believed to contribute to the etiology of chronic disorders like Alzheimer's disease and diabetes, thus supporting therapeutic potential of GSK-3 inhibitors. However, sustained GSK-3 inhibition might induce tumorigenesis through beta-catenin-APC dysregulation. Besides, sustained in vivo inhibition by genetic means (constitutive knock-out mice) revealed unexpected embryonic lethality due to massive hepatocyte apoptosis. Here, we have generated transgenic mice with conditional (tetracycline system) expression of dominant-negative-GSK-3 as an alternative genetic approach to predict the outcome of chronic GSK-3 inhibition, either per se, or in combination with mouse models of disease. By choosing a postnatal neuron-specific promoter, here we specifically address the neurological consequences. Tet/DN-GSK-3 mice showed increased neuronal apoptosis and impaired motor coordination. Interestingly, DN-GSK-3 expression shut-down restored normal GSK-3 activity and re-established normal incidence of apoptosis and motor coordination. These results reveal the importance of intact GSK-3 activity for adult neuron viability and physiology and warn of potential neurological toxicity of GSK-3 pharmacological inhibition beyond physiological levels. Interestingly, the reversibility data also suggest that unwanted side effects are likely to revert if excessive GSK-3 inhibition is halted. 相似文献
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Chiocco MJ Kulnane LS Younkin L Younkin S Evin G Lamb BT 《The Journal of biological chemistry》2004,279(50):52535-52542
Amyloid-beta (Abeta) the primary component of the senile plaques found in Alzheimer's disease (AD) is generated by the rate-limiting cleavage of amyloid precursor protein (APP) by beta-secretase followed by gamma-secretase cleavage. Identification of the primary beta-secretase gene, BACE1, provides a unique opportunity to examine the role this unique aspartyl protease plays in altering Abeta metabolism and deposition that occurs in AD. The current experiments seek to examine how modulating beta-secretase expression and activity alters APP processing and Abeta metabolism in vivo. Genomic-based BACE1 transgenic mice were generated that overexpress human BACE1 mRNA and protein. The highest expressing BACE1 transgenic line was mated to transgenic mice containing human APP transgenes. Our biochemical and histochemical studies demonstrate that mice overexpressing both BACE1 and APP show specific alterations in APP processing and age-dependent Abeta deposition. We observed elevated levels of Abeta isoforms as well as significant increases of Abeta deposits in these double transgenic animals. In particular, the double transgenics exhibited a unique cortical deposition profile, which is consistent with a significant increase of BACE1 expression in the cortex relative to other brain regions. Elevated BACE1 expression coupled with increased deposition provides functional evidence for beta-secretase as a primary effector in regional amyloid deposition in the AD brain. Our studies demonstrate, for the first time, that modulation of BACE1 activity may play a significant role in AD pathogenesis in vivo. 相似文献
10.
Enterostatin (APGPR) is a pentapeptide released from its precursor protein, procolipase. We found for the first time that enterostatin has memory-enhancing activity. Enterostatin enhanced memory consolidation after central or oral administration at a dose of 10 nmol/mouse or 300 mg/kg, respectively, in a step-through type passive avoidance test in mice. The memory-enhancing activity of enterostatin was inhibited by pretreatment with lorglumide, an antagonist for cholecystokinin 1 (CCK1) receptor. However, enterostatin had no affinity for CCK receptors. These results suggest that enterostatin improves memory retention through CCK release. 相似文献
11.
Memory consolidation for a trained sequence of finger opposition movements, in 9- and 12-year-old children, was recently found to be significantly less susceptible to interference by a subsequent training experience, compared to that of 17-year-olds. It was suggested that, in children, the experience of training on any sequence of finger movements may affect the performance of the sequence elements, component movements, rather than the sequence as a unit; the latter has been implicated in the learning of the task by adults. This hypothesis implied a possible childhood advantage in the ability to transfer the gains from a trained to the reversed, untrained, sequence of movements. Here we report the results of transfer tests undertaken to test this proposal in 9-, 12-, and 17-year-olds after training in the finger-to-thumb opposition sequence (FOS) learning task. Our results show that the performance gains in the trained sequence partially transferred from the left, trained hand, to the untrained hand at 48-hours after a single training session in the three age-groups tested. However, there was very little transfer of the gains from the trained to the untrained, reversed, sequence performed by either hand. The results indicate sequence specific post-training gains in FOS performance, as opposed to a general improvement in performance of the individual, component, movements that comprised both the trained and untrained sequences. These results do not support the proposal that the reduced susceptibility to interference, in children before adolescence, reflects a difference in movement syntax representation after training. 相似文献
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13.
7,8-dihydroxyflavone (7,8-DHF) has recently been identified as a potential TrkB agonist that crosses the blood-brain barrier after i.p. administration. We previously demonstrated that 7,8-DHF in vitro rescues long-term synaptic plasticity in the hippocampus of aged rats. This study assessed the rescue effect of 7,8-DHF in vivo on aging-related cognitive impairment in rats, and further determined whether the effect of 7,8-DHF is age dependent. Aged rats at 22 and 30 months of age were pretested for spatial memory in Morris water maze. The aged-impaired rats were retested twice during 7,8-DHF or vehicle treatment, which started 3 weeks after the completion of the pretest. In the 22-month-old rats, daily i.p. administration of 7,8-DHF for 2 weeks improved spatial memory. The improvement in behavioral tests was associated with increases in synapse formation and facilitation of synaptic plasticity in the hippocampus, as well as the activation of several proteins crucial to synaptic plasticity and memory. A more extended treatment paradigm with 7,8-DHF was required to achieve a significant memory improvement in the severely impaired 30-month-old rats. Moreover, 7,8-DHF moderately facilitated the synaptic plasticity, modified the density but not number of spines in the hippocampus of the oldest rats. Taken together, our results suggest that 7,8-DHF can act in vivo to counteract aging-induced declines in spatial memory and synaptic plasticity and morphological changes of hippocampal neurons. The effect of 7,8-DHF is more pronounced in relatively younger impaired rats than in those of more advanced age. These findings demonstrate the reversal of age-dependent memory impairment by in vivo 7,8-DHF application and support the benefit of early treatment for cognitive aging. 相似文献
14.
Kirchhefer U Baba HA Kobayashi YM Jones LR Schmitz W Neumann J 《American journal of physiology. Heart and circulatory physiology》2002,283(4):H1334-H1343
Triadin 1 is a protein in the cardiac junctional sarcoplasmic reticulum (SR) that interacts with the ryanodine receptor, junctin, and calsequestrin, proteins that are important for Ca(2+) release. To better understand the role of triadin 1 in SR-Ca(2+) release, we studied the time-dependent expression of SR proteins and contractility in atria of 3-, 6-, and 18-wk-old transgenic mice overexpressing canine cardiac triadin 1 under control of the alpha-myosin heavy chain (MHC) promoter. Three-week-old transgenic atria exhibited mild hypertrophy. Finally, atrial weight was increased by 110% in 18-wk-old transgenic mice. Triadin 1 overexpression was accompanied by time-dependent changes in the protein expression of the ryanodine receptor, junctin, and cardiac/slow-twitch muscle SR Ca(2+)-ATPase isoform. Force of contraction was already decreased in 3-wk-old transgenic atria. The application of caffeine led to a positive inotropic effect in transgenic atria of 3-wk-old mice. Rest pauses resulted in an increased potentiation of force of contraction after restimulation in 3- and 6-wk-old mice and a reduced potentiation of force of contraction in 18-wk-old transgenic mice. Hence, triadin 1 overexpression triggered time-dependent alterations in SR protein expression, Ca(2+) homeostasis, and contractility, indicating for the first time an inhibitory function of triadin 1 on SR-Ca(2+) release in vivo. 相似文献
15.
Kirchhefer U Neumann J Baba HA Begrow F Kobayashi YM Reinke U Schmitz W Jones LR 《The Journal of biological chemistry》2001,276(6):4142-4149
Triadin 1 is a major transmembrane protein in cardiac junctional sarcoplasmic reticulum (SR), which forms a quaternary complex with the ryanodine receptor (Ca(2+) release channel), junctin, and calsequestrin. To better understand the role of triadin 1 in excitation-contraction coupling in the heart, we generated transgenic mice with targeted overexpression of triadin 1 to mouse atrium and ventricle, employing the alpha-myosin heavy chain promoter to drive protein expression. The protein was overexpressed 5-fold in mouse ventricles, and overexpression was accompanied by cardiac hypertrophy. The levels of two other junctional SR proteins, the ryanodine receptor and junctin, were reduced by 55% and 73%, respectively, in association with triadin 1 overexpression, whereas the levels of calsequestrin, the Ca(2+)-binding protein of junctional SR, and of phospholamban and SERCA2a, Ca(2+)-handling proteins of the free SR, were unchanged. Cardiac myocytes from triadin 1-overexpressing mice exhibited depressed contractility; Ca(2+) transients decayed at a slower rate, and cell shortening and relengthening were diminished. The extent of depression of cell shortening of triadin 1-overexpressing cardiomyocytes was rate-dependent, being more depressed under low stimulation frequencies (0.5 Hz), but reaching comparable levels at higher frequencies of stimulation (5 Hz). Spontaneously beating, isolated work-performing heart preparations overexpressing triadin 1 also relaxed at a slower rate than control hearts, and failed to adapt to increased afterload appropriately. The fast time inactivation constant, tau(1), of the l-type Ca(2+) channel was prolonged in transgenic cardiomyocytes. Our results provide evidence for the coordinated regulation of junctional SR protein expression in heart independent of free SR protein expression, and furthermore suggest an important role for triadin 1 in regulating the contractile properties of the heart during excitation-contraction coupling. 相似文献
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The neuronal protein tyrosine phosphatases encoded by mouse gene Ptprr (PTPBR7, PTP-SL, PTPPBSgamma-42 and PTPPBSgamma-37) have been implicated in mitogen-activated protein (MAP) kinase deactivation on the basis of transfection experiments. To determine their physiological role in vivo, we generated mice that lack all PTPRR isoforms. Ptprr-/- mice were viable and fertile, and not different from wildtype littermates regarding general physiology or explorative behaviour. Highest PTPRR protein levels are in cerebellum Purkinje cells, but no overt effects of PTPRR deficiency on brain morphology, Purkinje cell number or dendritic branching were detected. However, MAP kinase phosphorylation levels were significantly altered in the PTPRR-deficient cerebellum and cerebrum homogenates. Most notably, increased phospho-ERK1/2 immunostaining density was observed in the basal portion and axon hillock of Ptprr-/- Purkinje cells. Concomitantly, Ptprr-/- mice displayed ataxia characterized by defects in fine motor coordination and balance skills. Collectively, these results establish the PTPRR proteins as physiological regulators of MAP kinase signalling cascades in neuronal tissue and demonstrate their involvement in cerebellum motor function. 相似文献
18.
Epigenetic mechanisms, including histone acetylation and DNA methylation, have been widely implicated in hippocampal-dependent learning paradigms. Here, we have examined the role of epigenetic alterations in amygdala-dependent auditory Pavlovian fear conditioning and associated synaptic plasticity in the lateral nucleus of the amygdala (LA) in the rat. Using Western blotting, we first show that auditory fear conditioning is associated with an increase in histone H3 acetylation and DNMT3A expression in the LA, and that training-related alterations in histone acetylation and DNMT3A expression in the LA are downstream of ERK/MAPK signaling. Next, we show that intra-LA infusion of the histone deacetylase (HDAC) inhibitor TSA increases H3 acetylation and enhances fear memory consolidation; that is, long-term memory (LTM) is enhanced, while short-term memory (STM) is unaffected. Conversely, intra-LA infusion of the DNA methyltransferase (DNMT) inhibitor 5-AZA impairs fear memory consolidation. Further, intra-LA infusion of 5-AZA was observed to impair training-related increases in H3 acetylation, and pre-treatment with TSA was observed to rescue the memory consolidation deficit induced by 5-AZA. In our final series of experiments, we show that bath application of either 5-AZA or TSA to amygdala slices results in significant impairment or enhancement, respectively, of long-term potentiation (LTP) at both thalamic and cortical inputs to the LA. Further, the deficit in LTP following treatment with 5-AZA was observed to be rescued at both inputs by co-application of TSA. Collectively, these findings provide strong support that histone acetylation and DNA methylation work in concert to regulate memory consolidation of auditory fear conditioning and associated synaptic plasticity in the LA. 相似文献
19.
Robust spatial working memory through homeostatic synaptic scaling in heterogeneous cortical networks 总被引:8,自引:0,他引:8
The concept of bell-shaped persistent neural activity represents a cornerstone of the theory for the internal representation of analog quantities, such as spatial location or head direction. Previous models, however, relied on the unrealistic assumption of network homogeneity. We investigate this issue in a network model where fine tuning of parameters is destroyed by heterogeneities in cellular and synaptic properties. Heterogeneities result in the loss of stored spatial information in a few seconds. Accurate encoding is recovered when a homeostatic mechanism scales the excitatory synapses to each cell to compensate for the heterogeneity in cellular excitability and synaptic inputs. Moreover, the more realistic model produces a wide diversity of tuning curves, as commonly observed in recordings from prefrontal neurons. We conclude that recurrent attractor networks in conjunction with appropriate homeostatic mechanisms provide a robust, biologically plausible theoretical framework for understanding the neural circuit basis of spatial working memory. 相似文献
20.
Repetitive DNA is known to undergo size variations based on an increase or decrease in the number of monomer units. We describe here the spontaneous expansion of an experimentally introduced tandem array of repeats in a transgenic mouse consisting of the human -actin promoter fused to the viral oncogene v-erbA and an SV40 polyadenylation signal (hAP/v-erbA). The expansion of the transgene was identified during routine screening of transgenic offspring for heterozygosity or homozygosity in one founder line. The control heterozygote genome consisted of the hAP/v-erbA transgene organized as a tandem array approximately five monomer units at a single chromosomal locus. The number of units increased to 20–21 copies, and germline transmission of the expanded units was stable for at least two generations. The majority of animals carrying the expanded monomer units retained their RNA expression patterns; however, some of these animals had drastically reduced expression levels. We discuss the possibility that expansion of repeated units may provide a mechanism by which the expression of a deleterious transgene is reduced. 相似文献