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PubMed1994

Genetic models of mammalian neural tube defects.

Several mouse mutations disturb the embryonic process of neurulation, yielding neural tube defects. Analysis of the mutations offers the most feasible approach to understanding the aetiology and pathogenesis of human neural tube defects. Interactions between the non-allelic mutant genes and between several of the mutant genes and modifying genes in the genetic background modulate the frequency and severity of the defects that develop. Environmental factors interact with the genetic predisposition either to increase or to decrease the incidence of defects. The gene loci corresponding to two of the mutations, splotch (Sp) and extra toes (Xt), have been identified as those encoding the transcription factors Pax-3 and Gli3, respectively; their human homologues are associated with Waardenburg type I syndrome and Greig's cephalopolysyndactyly. Embryological analysis reveals that several of the mutations disturb the process of neural tube closure at the posterior neuropore (in the lumbosacral region), yielding spina bifida and/or tail defects. The different mutations appear to achieve this developmental end-point by different underlying mechanisms. In curly tail (ct), non-neural tissues proliferate abnormally slowly causing ventral curvature of the neuropore region and inhibiting neural tube closure. Neural tube defects can be prevented in cultured ct/ct embryos by experimentally correcting either the proliferative imbalance or the ventral curvature. In Sp the primary defect appears to reside in the neuroepithelium. A combination of genetic analysis, gene cloning and experimental embryology is revealing that neural tube defects in mice and, by implication, in humans are a developmentally heterogeneous group of malformations.

Animals↗
PubMed2001

Medium-voltage 5-9-Hz oscillations give rise to spike-and-wave discharges in a genetic model of absence epilepsy: in vivo dual extracellular recording of thalamic relay and reticular neurons.

In humans with absence epilepsy, spike-and-wave discharges develop in the thalamocortical system during quiet immobile wakefulness or drowsiness. The present study examined the initial stage of the spontaneous development of spike-and-wave discharges in Genetic Absence Epilepsy Rats from Strasbourg. Bilateral electrocorticograms were recorded in epileptic and non-epileptic rats under freely moving and undrugged conditions and under neuroleptanalgesia. Short-lasting episodes of medium-voltage 5-9-Hz (mean=6-Hz) oscillations usually emerged spontaneously from a desynchronized electrocorticogram and in bilateral synchrony in both rat strains. These oscillations were distinguishable from sleep spindles regarding their internal frequency, duration, morphology, and moment of occurrence. Spontaneous spike-and-wave discharges developed from such synchronized medium-voltage oscillations, the spike-and-wave complex occurring at the same frequency as the 5-9-Hz wave. Because the thalamus is thought to play a significant role in the generation of spike-and-wave discharges, dual extracellular recording and juxtacellular labelling of relay and reticular neurons were conducted to study the thalamic cellular mechanisms associated with the generation of spike-and-wave discharges. During medium-voltage 5-9-Hz oscillations, discharges of relay and reticular cells had identical patterns in epileptic and non-epileptic rats, consisting of occasional single action potentials and/or bursts (interburst frequency of up to 6-8 Hz) in relay cells, and of rhythmic bursts (up to 12-15 Hz) in reticular neurons, these discharging in the burst mode almost always before relay neurons. The discharge frequency of reticular bursts decelerated to 6 Hz by the beginning of the spike-and-wave discharges. During these, relay and reticular neurons usually fired in synchrony a single action potential or a high-frequency burst of two or three action potentials and a high-frequency burst, respectively, about 12 ms before the spike component of the spike-and-wave complexes. The frequency of these corresponded to the maximal frequency of the thalamocortical burst discharges associated with 5-9-Hz oscillations. The patterns of relay and reticular phasic cellular firings associated with spike-and-wave discharges had temporal characteristics similar to those associated with medium-voltage 5-9-Hz oscillations, suggesting that these normal and epileptic oscillations are underlain by similar thalamic cellular mechanisms. In conclusion, medium-voltage 5-9-Hz oscillations in the thalamocortical loop give rise to spike-and-wave discharges. Such oscillations are not themselves sufficient to initiate spike-and-wave discharges, meaning that genetic factors render thalamocortical networks prone to generate epileptic electrical activity, possibly by decreasing the excitability threshold in reticular cells. While these GABAergic neurons play a key role in the synchronization of glutamatergic relay neurons during seizures, relay cells may participate significantly in the regulation of the recurrence of the spike-and-wave complex. Furthermore, it is very likely that synchronization of relay and reticular cellular discharges during absence seizures is generated in part by corticothalamic inputs.

Action Potentials↗
PubMed1993

Evidence for and against the Naples high- and low-excitability rats as genetic model to study hippocampal functions.

The Naples high- (NHE) and low-excitability (NLE) are two rat lines, selectively bred for high and low activity levels in a Làt-maze, respectively. Because the activity level in a novel environment depends mainly on the integrity of the hippocampal formation, and NLE and NHE rats differ with a similar background of emotionality, arterial blood pressure, and learning ability, they have been proposed as animal model to study hippocampal functions. Our aim is to prove evidence in favor and against this hypothesis. The evidence in favor indicates that NLE/NHE rats have a defective spatial processing, and pertains to (a) Differential activity in a spatial novelty situation (selection trait), proportional to the stimulus complexity rats are exposed to (NHE are hyper- and NLE-rats hypoactive); and (b) Impaired working memory in a six-arm non-reinforced tunnel maze in both lines compared to random-bred rats, that was reversed by the introduction of a reinforcer. In addition, multiple evidence of (i) lower intra- + infrapyramidal mossy fiber terminals in both NLE/NHE vs. controls; (ii) increased sensitivity of hippocampal elements to microinjections of vasopressin (but not oxytocin) and of "delta" (but not "mu") opioids; (iii) lower number of high-affinity glucocorticoid receptors; (iv) lower number of alpha- but not beta-adrenergic receptors in the hippocampus and hypothalamus of NHE rats only; and (v) the genotype-dependent behavior of a DNA fraction with fast turnover, suggest that both NHE/NLE are "disintegrated" at the hippocampal interface. Further, neurobehavioral covariations among individual differences reveal nonlinear, complex relationships, an evidence apparently against the hypothesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

The roles of prolactin, growth hormone, insulin-like growth factor-I, and thyroid hormones in lymphocyte development and function: insights from genetic models of hormone and hormone receptor deficiency.

An extensive literature suggesting that PRL, GH, IGF-I, and thyroid hormones play an important role in immunity has evolved. Because the use of one or more of these hormones as immunostimulants in humans is being considered, it is of critical importance to resolve their precise role in immunity. This review addresses new experimental evidence from analysis of lymphocyte development and function in mice with genetic defects in expression of these hormones or their receptors that calls into question the presumed role played by some of these hormones and reveals unexpected effects of others. These recent findings from the mutant mouse models are integrated and placed in context of the wider literature on endocrine-immune system interactions. The hypothesis that will be developed is that, with the exception of a role for thyroid hormones in B cell development, PRL, GH, and IGF-I are not obligate immunoregulators. Instead, they apparently act as anabolic and stress-modulating hormones in most cells, including those of the immune system.

Animals↗
PubMed2002

Input dysfunction, schizotypy, and genetic models of schizophrenia.

Peter Venables proposed that an input dysfunction, which causes the brain to lose its ability to control the flood of sensory information into its higher level processing areas, might be an important pathophysiological mechanism in schizophrenia. The hypothesis was part of his general belief that even the most severe psychopathology arises from aberrations in normal brain psychophysiology. Neurobiological and genetic investigations based on his initial observations include the demonstration that diminished inhibition of the auditory-evoked response to repeated stimuli is a genetically determined deficit, linked to one of the chromosomal loci that is also responsible for the part of the genetically transmitted risk for schizophrenia. Increasing evidence that schizophrenia is a multigenetic illness prompts reconsideration of the nature of schizotypy. Individual genes that convey part of the risk for schizophrenia may be quite common in the general population and cause relatively subtle changes in psychophysiology. Thus, as predicted by Venables, the substrates of schizotypy and schizophrenia may arise from variants in normal brain function.

Adult↗
PubMed1995

The role of the inferior colliculus in a genetic model of audiogenic seizures.

Previous studies have shown the functional importance of the inferior colliculus (IC) for the propagation and initiation of audiogenic seizures in several models of epilepsy in rats. A review of the cell types and cytoarchitecture of the IC, including its three major subdivisions, is presented. Significant increases in GABA levels and the number of GABAergic neurons are found in the central nucleus of the IC (ICCN) of genetically epilepsy-prone rats (GEPR-9s) as compared to Sprague-Dawley rats that do not display audiogenic seizures. Two independent anatomical methods were used to determine the number of GABAergic neurons, immunocytochemistry and in situ hybridization. In both types of preparation, the labeled cells in the ICCN appeared to be of different sizes but the number of small cells with diameters less than 15 microns showed the greatest increase. Nissl-stained sections showed that the total number of neurons in the ICCN was increased in GEPR-9s and indicated that the increase in GABAergic neurons was not due to a change in the phenotype of collicular neurons from non-GABAergic to GABAergic. The number of small neurons in Nissl-stained sections of the ICCN was shown to correlate with seizure severity in the offspring of crosses made between Sprague-Dawley rats and GEPR-9s. Furthermore, the GEPR-3s that display moderate seizures showed a significant increase in the number of small neurons in the ICCN, and the magnitude of this increase was predicted from this correlation. Finally, the use of knife cuts through the midbrain indicated that the ICCN sends an important projection to the external nucleus and that this projection plays a vital role in the propagation of seizure activity from the site of seizure initiation in the ICCN. It remains to be resolved how the increase in small GABAergic neurons in the ICCN is responsible for the known pharmacological defects observed at GABAergic synapses.

Acoustic Stimulation↗
PubMed2003

Drosophila melanogaster, a genetic model system for alcohol research.

In its natural environment, which consists of fermenting plant materials, the fruit fly Drosophila melanogaster encounters high levels of ethanol. Flies are well equipped to deal with the toxic effects of ethanol; they use it as an energy source and for lipid biosynthesis. The primary ethanol-metabolizing pathway in flies involves the enzymes alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH); their role in adaptation to ethanol-rich environments has been studied extensively. The similarity between Drosophila and mammals is not restricted to the manner in which they metabolize ethanol; behaviors elicited by ethanol exposure are also remarkably similar in these organisms. Flies show signs of acute intoxication, which range from locomotor stimulation at low doses to complete sedation at higher doses, they develop tolerance upon intermittent ethanol exposure, and they appear to like ethanol, showing preference for ethanol-containing media. Molecular genetic analysis of ethanol-induced behaviors in Drosophila, while still in its early stages, has already revealed some surprising parallels with mammals. The availability of powerful tools for genetic manipulation in Drosophila, together with the high degree of conservation at the genomic level, make Drosophila a promising model organism to study the mechanism by which ethanol regulates behavior and the mechanisms underlying the organism's adaptation to long-term ethanol exposure.

Alcohol Dehydrogenase↗
PubMed1987

Hemifacial deficiency induced by a shift in dominance of the mouse mutation far: a possible genetic model for hemifacial microsomia.

Hemifacial deficiency appeared in 10% of juvenile mice when BALB/cGaBc mice carrying the recessive lethal mutation far were crossed with ICR/Bc. The hemifacial deficiency increased to 15-20% after one backcross to ICR/Bc and then remained at that level for 11 additional generations of backcrossing of far into ICR/Bc. Neither the ICR/Bc strain nor BALB/cGaBc (+/far) produces hemifacial deficiency. Genetic and anatomical studies of adults and fetuses showed that the hemifacial deficiency was due to +/far in the ICR/Bc strain genome; that is, far becomes an incomplete dominant in the ICR/Bc strain background. The hemifacial deficiency (38% of +/far) is probably caused by premature synostosis of the maxilla and premaxilla, observable on day 16 of gestation. An additional 20% of +/far in ICR/Bc have cleft palate and die at birth. Most +/far in both strains have a hidden anomaly, bilateral splitting of the maxillary branch of the trigeminal nerve. far/far homozygotes of both strain backgrounds have a syndrome of severe bilateral deficiency of the derivatives of the maxillary prominence. In human pedigrees, where the equivalents of the dominance modifiers in BALB/cGaBc and ICR/Bc would segregate within families, it would be difficult to recognize that sporadic hemifacial deficiency and severe bilateral maxillary deficiency were due to the same gene. We suggest that human bilateral and unilateral abnormalities of tissue derived from the first branchial arch should be analyzed with the awareness that, in mice, at least, the two kinds of syndrome are due to the same mutant gene.

Animals↗
PubMed1980

Niemann-Pick disease: a genetic model in Siamese cats.

Three Siamese cats were found to have a progressive neurological disease that became obvious when they were 4 to 5 months of age. Their brains contained an excess of GM2 and GM3 gangliosides, and their livers a nine- to tenfold excess of sphingomyelin and cholesterol. A total deficiency of lysosomal (pH 5.0) sphingomyelinase was found in the leukocytes, liver, and brain of the cats, although the activity of the microsomal (pH 7.4, magnesium-dependent) sphingomyelinase was normal in brain. These cats appear to have a genetic disease identical to Niemann-Pick disease type A.

Animals↗
PubMed2002

Genetic models meet trophic mechanisms: EGF family members are gliatrophins in Drosophila.

Trophic survival mechanisms are crucial for the determination of cell numbers in the developing vertebrate nervous system, but important neurotrophic factor families such as the neurotrophins have not yet been found in either Drosophila or C. elegans. Two independent studies on distinct glial populations in Drosophila have now shown that their survival is regulated by EGF family members secreted by adjacent neurons. Fly genetics thus promises new insights on trophic signaling mechanisms and confirms that trophic regulation of cell survival is an evolutionarily ancient mechanism for building the nervous system.

Animals↗
PubMed2003

A transgenic mouse model genetically tags all activated CD8 T cells.

Identifying and characterizing Ag-specific CD8+ T cells are central to the study of immunological memory. Although powerful strategies such as MHC tetramers and peptide-induced cytokine production assays exist for identifying Ag-specific CD8+ T cells, alternate strategies that are not dependent upon a priori knowledge of the immunodominant and subdominant antigenic epitopes, as well as the MHC background of the animal are of obvious utility. In this study, we present a transgenic mouse model that uses Cre-loxP recombination to permanently mark all activated CD8+ T cells with beta-galactosidase. We used the lymphocytic choriomeningitis virus infection model to track the dynamics of the antiviral CD8+ T cell responses. We show that in this transgenic mouse model system, all of the antiviral effector and memory CD8+ T cells are contained within the beta-gal-marked CD8+ T cell population.

Animals↗
PubMed2002

Rosiglitazone improves insulin resistance, lipid profile and promotes adiposity in a genetic model of metabolic syndrome X.

RSG is a member of the TZD group of drugs widely used in treatment of type 2 diabetes. The underlying mechanism of TZD action in insulin-sensitive tissues is not fully understood. In this study we show that 14-day RSG administration in a new rodent model of metabolic syndrome X, polydactylous rat strain (PD/Cub), substantially improves its lipid profile (serum TGs 4.20 +/- 0.23 vs 2.34 +/- 0.14 mmol/l, P < 0.0001; FFA 0.46 +/- 0.05 vs 0.33 +/- 0.02 mmol/l, P = 0.017), diminishes the liver TG depots (15.76 +/- 0.60 vs 8.44 +/- 0.55 micromol/g, P < 0.0001), serum insulin concentrations (1.10 +/- 0.08 vs 0.63 +/- 0.02 nmol/l, P < 0.0001) and promotes visceral adiposity (adiposity index 1.28 +/- 0.03 vs 1.85 +/- 0.07, P < 0.0001). No changes were observed in serum or liver concentrations of cholesterol. Concomitantly, both basal and insulin-stimulated glycogen synthesis in red-fibre type muscle (m. soleus) was enhanced, as well as glucose uptake into adipose tissue. However, glucose oxidation in soleus (basal and insulin-stimulated) remained unchanged. In consent with previously published data we suggest the current pharmacogenetic study as a further proof of substantial influence of genetic background on the physiological outcome of TZD therapy.

Adipose Tissue↗
PubMed2000

Genetic models reveal that brain natriuretic peptide can signal through different tissue-specific receptor-mediated pathways.

Brain natriuretic peptide (BNP), a hormone produced primarily by the cardiac ventricle, is thought to be involved in a variety of homeostatic processes through its cognate receptor, guanylyl cyclase A (GC-A). We previously created transgenic mice overexpressing BNP under the control of the liver-specific human serum amyloid P component promoter (BNP-transgenic mice) and demonstrated that they exhibit reduced blood pressure and cardiac weight accompanied by an elevation of plasma cGMP concentrations and marked skeletal overgrowth through the activation of endochondral ossification. To address whether BNP exerts its biological effects solely through GC-A, we produced BNP-transgenic mice lacking GC-A (BNP-Tg/GC-A-/- mice) and examined their cardiovascular and skeletal phenotypes. The GC-A-/- mice are hypertensive with cardiac hypertrophyrelative to wild-type littermates, which is not alleviated by overexpression of BNP in BNP-Tg/GC-A-/- mice. The BNP-Tg/GC-A-/- mice, however, continue to exhibit marked longitudinal growth of vertebrae and long bones comparably to BNP-Tg mice. This study provides genetic evidence that BNP reduces blood pressure and cardiac weight through GC-A, whereas it dramatically alters endochondral ossification in the absence of this receptor. Therefore, the BNP-Tg/GC-A-/- mice provide the first experimental model demonstrating that this natriuretic peptide can signal in a tissue-specific manner through a receptor other than GC-A.

Animals↗
PubMed2002

Evidence for vestibular regulation of autonomic functions in a mouse genetic model.

Physiological responses to changes in the gravitational field and body position, as well as symptoms of patients with anxiety-related disorders, have indicated an interrelationship between vestibular function and stress responses. However, the relative significance of cochlear and vestibular information in autonomic regulation remains unresolved because of the difficulties in distinguishing the relative contributions of other proprioceptive and interoceptive inputs, including vagal and somatic information. To investigate the role of cochlear and vestibular function in central and physiological responses, we have examined the effects of increased gravity in wild-type mice and mice lacking the POU homeodomain transcription factor Brn-3.1 (Brn-3bPou4f3). The only known phenotype of the Brn-3.1(-/-) mouse is related to hearing and balance functions, owing to the failure of cochlear and vestibular hair cells to differentiate properly. Here, we show that normal physiological responses to increased gravity (2G exposure), such as a dramatic drop in body temperature and concomitant circadian adjustment, were completely absent in Brn-3.1(-/-) mice. In line with the lack of autonomic responses, the massive increase in neuronal activity after 2G exposure normally detected in wild-type mice was virtually abolished in Brn-3.1(-/-) mice. Our results suggest that cochlear and vestibular hair cells are the primary regulators of autonomic responses to altered gravity and provide genetic evidence that these cells are sufficient to alter neural activity in regions involved in autonomic and neuroendocrine control.

Animals↗
PubMed2003

Genetic models in applied physiology: invited review: effect of oxygen deprivation on cell cycle activity: a profile of delay and arrest.

One of the most fascinating fields that have emanated in the past few decades is developmental biology. This is not only the case from a research point of view but also from the angle of clinical care and treatment strategies. It is now well demonstrated that there are many diseases (some believe all diseases) that have their roots in embryogenesis or in early life, where nature and environment often team up to facilitate the genesis of disease. There is probably no better example to illustrate the interactions between nature and environment than in early life, as early as in the first several cell cycles. As will be apparent in this review, the cell cycle is a very regulated activity and this regulation is genetic in nature, with checkpoint proteins playing an important role in controlling the timing, the size, and the growth of daughter cells. However, it is also very clear, as will be discussed in this work, that the microenvironment of the first dividing cells is so important for the outcome of the organism. In this review, we will focus on the effect of one stress, that of hypoxia, on the young embryo and its cell division and growth. We will first review some of the cell cycle definitions and stages and then review briefly our current knowledge and its gaps in this area.

Animals↗