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PubMed2006

A novel genetic model of selective COX-2 inhibition: comparison with COX-2 null mice.

Prostaglandin H Synthase (PGHS) is a bi-functional enzyme with a cyclooxygenase (COX) activity and a functionally linked peroxidase (POX) activity that exists in two isoforms (COX-1, COX-2). Non-steroidal anti-inflammatory drugs (NSAIDs), including the selective COX-2 inhibitors, block COX activity while leaving POX activity unscathed. Recently, some selective COX-2 inhibitors were withdrawn from the market due to elevated cardiovascular risk in placebo-controlled trials. Mice deficient for PGHS2 were developed in 1995 and through numerous subsequent studies have revealed significant roles in renal development, ductus arteriosus patency/closure, skin carcinogenesis and cardiovascular function. In this short review, we compare a novel genetic COX-2 selective inhibition mouse model with the originally described COX-2 null mice in these different physiological functions.

Amino Acid Substitution↗
PubMed1995

Mesopontine cholinergic control over generalized non-convulsive seizures in a genetic model of absence epilepsy in the rat.

Pharmacological data have shown that the cholinergic transmission participates in the control of spike-and-wave discharges in rats with genetic absence epilepsy. The corticothalamic circuitry which generates spontaneous spike-and-wave discharges, the electroencephalographic expression of absence seizures, receives important cholinergic inputs from two distinct sources: (i) the nucleus basalis projecting mainly to the cortex and (ii) the pedunculopontine and laterodorsal tegmental nuclei providing cholinergic afferents to the thalamus. In the present study, the involvement of the cholinergic mesopontothalamic projections in the control of spike-and-wave discharges was investigated. Activation of cell bodies in the pedunculopontine and laterodorsal tegmental nuclei, by local microinjections of non-toxic doses of kainate (20 pmol/side) or picrotoxin (66 pmol/side), suppressed spike-and-wave discharges. Similar effects were produced by direct cholinergic activation of the ventrolateral part of the thalamus: intrathalamic microinjections of carbachol (0.7-2.8 pmol/side), a cholinergic receptor agonist, resulted in a dose-dependent suppression of spike-and-wave discharges. This suppression was partially reversed by a simultaneous microinjection of an equimolar dose of scopolamine, a muscarinic receptor antagonist. Electrolytic or neuroexcitotoxic lesions of the pedunculopontine and laterodorsal tegmental nuclei did not modify spike-and-wave discharges. These results suggest that the cholinergic mesopontine projection to the thalamus exerts a phasic inhibitory control of generalized non-convulsive epileptic seizures.

Animals↗
PubMed2001

Genetic modelling of test day records in dairy sheep using orthogonal Legendre polynomials.

Test day milk yields of three lactations in Sfakia sheep were analyzed fitting a random regression (RR) model, regressing on orthogonal polynomials of the stage of the lactation period, i.e. days in milk. Univariate (UV) and multivariate (MV) analyses were also performed for four stages of the lactation period, represented by average days in milk, i.e. 15, 45, 70 and 105 days, to compare estimates obtained from RR models with estimates from UV and MV analyses. The total number of test day records were 790, 1314 and 1041 obtained from 214, 342 and 303 ewes in the first, second and third lactation, respectively. Error variances and covariances between regression coefficients were estimated by restricted maximum likelihood. Models were compared using likelihood ratio tests (LRTs). Log likelihoods were not significantly reduced when the rank of the orthogonal Legendre polynomials (LPs) of lactation stage was reduced from 4 to 2 and homogenous variances for lactation stages within lactations were considered. Mean weighted heritability estimates with RR models were 0.19, 0.09 and 0.08 for first, second and third lactation, respectively. The respective estimates obtained from UV analyses were 0.14, 0.12 and 0.08, respectively. Mean permanent environmental variance, as a proportion of the total, was high at all stages and lactations ranging from 0.54 to 0.71. Within lactations, genetic and permanent environmental correlations between lactation stages were in the range from 0.36 to 0.99 and 0.76 to 0.99, respectively. Genetic parameters for additive genetic and permanent environmental effects obtained from RR models were different from those obtained from UV and MV analyses.

Journal Article↗
PubMed1990

A genetic model for evaluation of susceptibility to ozone-induced inflammation.

We examined ozone-induced airway inflammatory responses in inbred mice, and progeny of crosses between them, to investigate genetic susceptibility to ozone. Nine strains of male mice (18-23 g, 5-7 wk) were exposed for 3 h to 2 ppm ozone (O3) or filtered air (control), and pulmonary inflammation was assessed 2, 6, and 24 h after exposure by inflammatory cell counts and total protein content in bronchoalveolar lavage (BAL). The time course of the response to O3 was consistent between the strains. The maximum change in polymorphonuclear leukocytes (PMNs) was detected 6 h after O3, and the maximum increase in BAL protein occurred 24 h postexposure. Air controls exhibited no detectable changes in the parameters of inflammation at any time. The phenotypes of the C57BL/6J (B6, termed susceptible) and C3H/HeJ (C3, termed resistant) strains were easily distinguished by the magnitude of their inflammatory responses to O3. A 22-fold difference in PMNs was detected between the two strains 2 h after O3 (P less than 0.001), and a sixfold difference was found 6 h after O3 (P less than 0.001). Total BAL proteins were also significantly different between the B6 and C3 strains 6 h (P less than 0.01) and 24 h after O3 (P less than 0.001). To further evaluate the potential genetic contribution to the inflammatory response, the F1, F2, and backcross progeny from crosses between B6 and C3 strains were examined. The phenotypes of these progeny were consistent with the hypothesis that a single autosomal recessive gene at the Inf locus confers susceptibility to acute O3-induced influx of PMNs, but the genetic control of altered permeability is not clear.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Gamma-aminobutyric acid uptake is decreased in the hippocampus in a genetic model of human temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is one of the most commonly occurring and most intractable forms of seizure disorders in humans. The fundamental mechanisms underlying the pathogenesis of the disorder have, however, not yet been elucidated. El is an inbred mouse strain with genetic predisposition to epileptic seizures. The El mouse epilepsy shares its main features with TLE in humans and is considered to be an excellent model of the latter. We report a marked decrease in the uptake of gamma-aminobutyric acid (GABA) in the hippocampus of El mice. The data favor the involvement of GABA and the hippocampus in the mechanisms of TLE and suggest a genetic basis for the altered GABA uptake. This is the first report suggesting the possibility of a hereditary defect of a neurotransmitter function in TLE.

Animals↗
PubMed2006

Assessment of plants from the Brassicaceae family as genetic models for the study of nickel and zinc hyperaccumulation.

We report on the second phase of a programme to select a relative of Arabidopsis thaliana for use in large-scale molecular genetic studies of nickel (Ni) and zinc (Zn) hyperaccumulation. We also report on the relatedness among Thlaspi caerulescens accessions and the utility of using O-acetyl-L-serine as a marker for Ni and Zn hyperaccumulation potential. Twenty-seven new accessions of metal-accumulating species collected in the Czech Republic, France, Greece, Italy, Slovenia and the USA during Spring-Summer 2002 were evaluated. The criteria established for selection were hyperaccumulation of metals (Ni and Zn); compact growth habit; reasonable time to flowering; production of > or = 1000 seeds per plant; self-fertility; compact diploid genome; high sequence similarity to A. thaliana; > or = 0.1% transformation efficiency with easy selection. We conclude that the best candidate identified in the first phase was the best candidate overall: T. caerulescens accession St Félix de Pallières.

Arabidopsis↗
PubMed2002

Genetic modeling of estrogen metabolism as a risk factor of hormone-dependent disorders.

Estradiol is a pleiotropic hormone, involved in the etiology of a wide variety of diseases. Over the last decade individual genetic variability of the estradiol metabolism has been described as a significant contributor to disease susceptibility with variations depending on ethnic background. Among others, genetic variations of genes encoding cytochrome P450 (CYP) enzymes play an important role in this regard. Mutant alleles of the CYP 1A1 gene are major modulators of lung cancer risk among smokers, mediate gender differences in lung cancer susceptibility, and have been associated with an elevated risk for breast, prostate, colorectal, and oral squamous cell cancer. Variants of the CYP 1B1 gene modulate the risk for prostate, ovarian, lung, and breast cancer. Also, mutations in the CYP 1B1 gene are the major genetic determinant of congenital glaucoma. Mutant CYP 17 alleles are associated with serum and plasma levels of steroid hormones, use of hormone replacement therapy, and endometrial, prostate, and breast cancer. Available data indicate that the protective effect of a later age at menarche is limited to mutant CYP 17 allele carriers. Among women with the Polycystic Ovary (PCO) syndrome, mutant CYP 17 alleles are sufficient to aggravate the clinical presentation of the disease. Molecular variants of the CYP 19 gene are associated with an increased risk for breast cancer, advanced disease stage, and tumor aromatase production. Carriage of a mutant catechol-O-methyltransferase (COMT) allele is associated with breast cancer, neurologic disorders such as Parkinson's disease, and modulates behavior among patients with schizophrenia, alcoholics and the general population. In summary, the available evidence points to estrogen metabolising genes as strong hereditary determinants of the susceptibility to benign and malignant conditions.

Breast Neoplasms↗
PubMed2005

Genetic models to study adult neurogenesis.

In the central nervous system (CNS) generation of new neurons continues throughout adulthood, when it is limited to the olfactory bulb and hippocampus. The knowledge regarding the function of newly-generated neurons remains limited and is vigorously investigated using diverse approaches. Among these are genetically modified mice, most of them of knock-out type (KO). Results from 23 diverse KO mouse models demonstrate the importance of particular proteins (growth factors, nitric oxide synthases, receptors, cyclins/cyclin-associated proteins, transcription factors, etc.) in adult neurogenesis (ANGE) as well as separate it from developmental neurogenesis. These results bring us closer to revealing the function of newly generated neurons in adult brains.

Animals↗
PubMed2002

Genetic modeling of glioma formation in mice.

In addition to the histological features that define gliomas, mutations and other alterations in gene expression and signal transduction are classically found in these tumors. Some of these alterations are likely to be the effects of the neoplastic phenotype, while others may be causative agents essential to the etiologic origin of the disease. The determination of whether specific genetic alterations, either individually or in combination, can serve as the etiology of gliomas requires modeling in animals with the fulfillment of Koch's postulates. Animal modeling studies not only provide information on the potential causes of glioma formation, they also identify novel candidate targets for therapy and provide tumor-bearing animals for preclinical trials. Recently, remarkable strides have been made in the generation of mouse models of the diffuse gliomas that provide unparalleled opportunities for advancing our knowledge of the etiology, maintenance, and treatment of this lethal class of tumors.

Animals↗
PubMed2001

Lack of mitochondrial anionic phospholipids causes an inhibition of translation of protein components of the electron transport chain. A yeast genetic model system for the study of anionic phospholipid function in mitochondria.

Reduction of mitochondrial cardiolipin (CL) levels has been postulated to compromise directly the function of several essential enzymes and processes of the mitochondria. There is limited genetic evidence for the critical roles with which CL and its precursor phosphatidylglycerol (PG) have been associated. A null allele of the PGS1 gene from Saccharomyces cerevisiae, which encodes the enzyme responsible for the synthesis of the CL precursor PG phosphate, was created in a yeast strain in which PGS1 expression is exogenously regulated by doxycycline. The addition of increasing concentrations of doxycycline to the growth medium causes a proportional decrease to undetectable levels of PGS1 transcript, PG phosphate synthase activity, and PG plus CL. The doubling time of this strain with increasing doxycycline increases to senescence in non-fermentable carbon sources or at high temperatures, conditions that do not support growth of the pgs1Delta strain. Doxycycline addition also causes mitochondrial abnormalities as observed by fluorescence microscopy. Products of four mitochondrial encoded genes (COX1, COX2, COX3, and COB) and one nuclear encoded gene (COX4) associated with the mitochondrial inner membrane are not present when PGS1 expression is fully repressed. No translation of these proteins can be detected in cells lacking the PGS1 gene product, although transcription and splicing appear unaffected. Protein import of other nuclear encoded proteins remains unaffected. The remaining proteins encoded by mitochondrial DNA are expressed and translated normally. Thus, the molecular basis for the lack of mitochondrial function in pgs1Delta cells is the failure to translate gene products essential to the electron transport chain.

Acridine Orange↗
PubMed1999

Superimposed histologic and genetic mapping of chromosome 9 in progression of human urinary bladder neoplasia: implications for a genetic model of multistep urothelial carcinogenesis and early detection of urinary bladder cancer.

The evolution of alterations on chromosome 9, including the putative tumor suppressor genes mapped to the 9p21-22 region (the MTS genes), was studied in relation to the progression of human urinary bladder neoplasia by using whole organ superimposed histologic and genetic mapping in cystectomy specimens and was verified in urinary bladder tumors of various pathogenetic subsets with longterm follow-up. The applicability of chromosome 9 allelic losses as non-invasive markers of urothelial neoplasia was tested on voided urine and/or bladder washings of patients with urinary bladder cancer. Although sequential multiple hits in the MTS locus were documented in the development of intraurothelial precursor lesions, the MTS genes do not seem to represent a major target for p21-23 deletions in bladder cancer. Two additional tumor suppressor genes involved in bladder neoplasia located distally and proximally to the MTS locus within p22-23 and p11-13 regions respectively were identified. Several distinct putative tumor suppressor gene loci within the q12-13, q21-22, and q34 regions were identified on the q arm. In particular, the pericentromeric q12-13 area may contain the critical tumor suppressor gene or genes for the development of early urothelial neoplasia. Allelic losses of chromosome 9 were associated with expansion of the abnormal urothelial clone which frequently involved large areas of urinary bladder mucosa. These losses could be found in a high proportion of urothelial tumors and in voided urine or bladder washing samples of nearly all patients with urinary bladder carcinoma.

Chromosome Aberrations↗
PubMed2000

The midline glia of Drosophila: a molecular genetic model for the developmental functions of glia.

The Midline Glia of Drosophila are required for nervous system morphogenesis and midline axon guidance during embryogenesis. In origin, gene expression and function, this lineage is analogous to the floorplate of the vertebrate neural tube. The expression or function of over 50 genes, summarised here, has been linked to the Midline Glia. Like the floorplate, the cells which generate the Midline Glia lineage, the mesectoderm, are determined by the interaction of ectoderm and mesoderm during gastrulation. Determination and differentiation of the Midline Glia involves the Drosophila EGF, Notch and segment polarity signaling pathways, as well as twelve identified transcription factors. The Midline Glia lineage has two phases of cell proliferation and of programmed cell death. During embryogenesis, the EGF receptor pathway signaling and Wrapper protein both function to suppress apoptosis only in those MG which are appropriately positioned to separate and ensheath midline axonal commissures. Apoptosis during metamorphosis is regulated by the insect steroid, Ecdysone. The Midline Glia participate in both the attraction of axonal growth cones towards the midline, as well as repulsion of growth cones from the midline. Midline axon guidance requires the Drosophila orthologs of vertebrate genes expressed in the floorplate, which perform the same function. Genetic and molecular evidence of the interaction of attractive (Netrin) and repellent (Slit) signaling is reviewed and summarised in a model. The Midline Glia participate also in the generation of extracellular matrix and in trophic interactions with axons. Genetic evidence for these functions is reviewed.

Animals↗
PubMed1997

Paroxysmal discharges in the EL mouse, a genetic model of epilepsy.

The EL/Suz (EL) mouse is a strain that is highly susceptible to convulsive seizures after repeated sensory stimulation. Its control strain, DDY/Jc1 (DDY), is less susceptible under similar conditions. The seizure prone phenotype is the result of differences at several genetic loci. In vivo electrical recordings from the seizure prone EL mouse brain have shown that the appearance of abnormal discharges in the hippocampus are critical to the onset of generalized seizures, indicating that the hippocampus plays an important role in EL mouse seizure activity. In the present study, electrophysiological differences between EL and DDY mice (9-15 weeks of age) were examined by comparing field potentials recorded from the dentate granule cell layer of hippocampal brain slices from mice that had not been stimulated to induce seizures. In control physiological solution, no significant differences were observed in characteristics of perforant path evoked field potentials or in paired pulse depression of evoked field potentials using 20 to 300 ms interstimulus intervals. After 60 min of disinhibition following bicuculline (10 microM) exposure, however, prolonged large amplitude potentials, paroxysmal discharges, were evoked by perforant path stimulation in the dentate gyrus of EL mice but were absent in the DDY strain. Paroxysmal discharges were curtailed by APV and were similar to responses recorded from the dentate gyrus in hippocampal brain slices from temporal lobe epileptic patients. The field response to hilar stimulation was identical in both strains and was composed of a single population spike before and after bicuculline exposure. Mossy fiber terminals were not present in the molecular layer of either strain. We propose that the mechanisms leading to a greater likelihood of paroxysmal discharge generation in EL mouse may be important in the development and/or generation of epileptic seizures in this mouse strain and may be a significant phenotypic difference between the EL mouse and its parent strain.

Animals↗
PubMed2006

Effects in vitro and in vivo of a gap junction blocker on epileptiform activities in a genetic model of absence epilepsy.

We investigated the effects of carbenoxolone (CBX), a gap junctions (GJ) blocker, on epileptiform activities in vivo and in vitro. In a first series of experiments, i.p. CBX decreased the cumulative duration of cortical spike-wave discharges (SWD) in adult Genetic Absence Epilepsy Rats from Strasbourg (GAERS) without reduction in the SW amplitude or frequency. Since SWD are generated in thalamocortical networks, we studied the effect of CBX on thalamic and cortical activities elicited by 4-aminopyridine (4AP) in thalamocortical slices from GAERS or non-epileptic rats (NER). Spontaneous ictal-like activities (ILA) were recorded simultaneously in thalamus and somatosensory cortex. However, experiments where these structures were surgically separated showed that ILA were generated in the cortex and recorded by volume conduction in the thalamus. GABA-dependent negative field potentials were also recorded in the cortex, either isolated or initiating ILA. After bath-applying CBX (100 microM), the frequency and cumulative duration of ILA decreased but less rapidly in GAERS than in NER slices and they disappeared at a time point when GABA-dependent negative potentials remained. These data suggest that GJ do not mediate the 4AP induced interneuronal synchronisation but may be implicated in the spreading of the synchronised activities from interneuronal networks to principal neurones. Our results show that CBX exerts an antiepileptic action in vivo, and that GJ blockers limits spread of synchronised activities in vitro. They may represent an appropriate target for development of new antiepileptic drugs.

4-Aminopyridine↗
PubMed1973

Genetic model for the Rh blood-group system.

Inherited quantitative aspects of the Rh blood-group system and susceptibility of Rh to the effects of independently segregating suppressor genes can be accounted for with a conjugated operon model. This assumes the existence of four operator or promotor (control) genes for these functions, while closely linked structural regions determine the qualitative characteristics of Rh antigens. Observed restriction of antigenic crossreactivity to the products of adjacent genetic regions and data from blood typing of nonhuman primates both suggest that Rh complexity arose from a series of gene duplications and independent mutations.

ABO Blood-Group System↗
PubMed1993

Thalamic low threshold calcium current in a genetic model of absence epilepsy.

The low threshold calcium current (IT) in thalamo-cortical neurones contributes to the generation of spike and wave discharges (SWDs) characteristic of generalized, non-convulsive absence epilepsy. The biophysical properties of this current were analysed in dorsal lateral geniculate neurones from the Genetic Absence Epilepsy Rats from Strasbourg (GAERS+). No difference was found in the voltage dependence and kinetics of IT between GAERS+ and rats of the non epileptic control strain (GAERS-). Thus, a dysfunction of IT does not appear to underlie the occurrence of SWDs in absence epilepsy.

Animals↗