RESUMO
Myelin is essential for efficient signal transduction in the nervous system comprising of multiple proteins. The intricacies of the regulation of the formation of myelin, and its components, are not fully understood. Here, we describe the characterization of a novel myelin basic protein (Mbp) mutant mouse, mbp(jive), which spontaneously occurred in our mouse colony. These mice displayed the onset of a shaking gait before 3 weeks of age and seizure onset before 2 months of age. Due to a progressive increase of seizure intensity, mbp(jive) mice experienced premature lethality at around 3 months of age. Mbp mRNA transcript or protein was undetectable and, accordingly, genetic analysis demonstrated a homozygous loss of exons 3 to 6 of Mbp. Peripheral nerve conductance was mostly unimpaired. Additionally, we observed grave structural changes in white matter predominant structures were detected by T1, T2 and diffusion weighted magnetic resonance imaging. We additionally observed that Mbp-deficiency results in an upregulation of Qkl, Mag and Cnp, suggestive of a regulatory feedback mechanism whereby compensatory increases in Qkl have downstream effects on Mag and Cnp. Further research will clarify the role and specifications of this myelin feedback loop, as well as determine its potential role in therapeutic strategies for demyelinating disorders.
Assuntos
Camundongos Mutantes/genética , Camundongos Mutantes/fisiologia , Proteína Básica da Mielina/genética , Bainha de Mielina/genética , Ativação Transcricional , Animais , Encéfalo/patologia , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/genética , Mutação , Fenótipo , Transdução de Sinais/genética , Regulação para Cima , Substância Branca/patologiaRESUMO
BACKGROUND: Modern molecular genetics create a rapidly growing number of mutant mouse lines, many of which need to be phenotyped behaviorally. Poor reliability and low efficiency of traditional behavioral tests have prompted the development of new approaches to behavioral phenotyping, such as fully automated analysis of behavior in the homecage. NEW METHOD: We asked whether the analysis of spontaneous behavior during the first week in the social homecage system IntelliCage could provide useful prescreening information before specialized and time consuming test batteries are run. To determine how much behavioral variation is captured in this data, we performed principal component analysis on free adaptation data of 1552 mice tested in the IntelliCage during the past years. We then computed individual component scores to characterize and compare groups of mice. RESULT: We found 11 uncorrelated components which accounted for 82% of total variance. They characterize frequency and properties of corner visits and nosepokes, drinking activity, spatial distribution, as well as diurnal time course of activity. Behavioral profiles created using individual component scores were highly characteristic for different inbred strains or different lesion models of the nervous system. They were also remarkably stable across labs and experiments. COMPARISON WITH EXISTING METHODS: Monitoring of mutant mice with known deficits in hippocampus-dependent tests produced profiles very similar to those of hippocampally lesioned mice. CONCLUSIONS: Taken together, our results suggest that already the monitoring of spontaneous behavior during a week of free adaptation in the IntelliCage can contribute significantly to high throughput prescreening of mutant mice.
Assuntos
Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Camundongos Endogâmicos/fisiologia , Camundongos Mutantes/fisiologia , Comportamento Social , Análise de Variância , Animais , Feminino , Camundongos , Camundongos Endogâmicos/genética , Camundongos Mutantes/genética , Fenótipo , Estudos Retrospectivos , Especificidade da EspécieRESUMO
Mechanisms of cerebellar motor learning are still poorly understood. The standard Marr-Albus-Ito theory posits that learning involves plasticity at the parallel fiber to Purkinje cell synapses under control of the climbing fiber input, which provides an error signal as in classical supervised learning paradigms. However, a growing body of evidence challenges this theory, in that additional sites of plasticity appear to contribute to motor adaptation. Here, we consider phase-reversal training of the vestibulo-ocular reflex (VOR), a simple form of motor learning for which a large body of experimental data is available in wild-type and mutant mice, in which the excitability of granule cells or inhibition of Purkinje cells was affected in a cell-specific fashion. We present novel electrophysiological recordings of Purkinje cell activity measured in naive wild-type mice subjected to this VOR adaptation task. We then introduce a minimal model that consists of learning at the parallel fibers to Purkinje cells with the help of the climbing fibers. Although the minimal model reproduces the behavior of the wild-type animals and is analytically tractable, it fails at reproducing the behavior of mutant mice and the electrophysiology data. Therefore, we build a detailed model involving plasticity at the parallel fibers to Purkinje cells' synapse guided by climbing fibers, feedforward inhibition of Purkinje cells, and plasticity at the mossy fiber to vestibular nuclei neuron synapse. The detailed model reproduces both the behavioral and electrophysiological data of both the wild-type and mutant mice and allows for experimentally testable predictions.
Assuntos
Adaptação Fisiológica/genética , Cerebelo/fisiologia , Aprendizagem/fisiologia , Camundongos Mutantes/fisiologia , Modelos Biológicos , Reflexo Vestíbulo-Ocular/genética , Animais , Cerebelo/citologia , Simulação por Computador , Movimentos Oculares/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Dinâmica não Linear , Células de Purkinje/fisiologia , Receptores de GABA/genética , Receptores de GABA-A , Simportadores/genética , Sinapses/genética , Cotransportadores de K e Cl-RESUMO
Rodent models are a key factor in the process of translating psychiatric genetics and genomics findings, allowing us to shed light on how risk-genes confer changes in neurobiology by merging different types of data across fields, from behavioural neuroscience to the burgeoning omics (e.g. genomics, epigenomics, proteomics, etc.). Moreover, they also provide an indispensable first step for drug discovery. However, recent evidence from both clinical and genetic studies highlights possible limitations in the current methods for classifying psychiatric illness, as both symptomology and underlying genetic risk are found to increasingly overlap across disorder diagnoses. Meanwhile, integration of data from animal models across disorders is currently limited. Here, we argue that behavioural neuroscience is in danger of missing informative data because of the practice of trying to 'diagnose' an animal model with a psychiatric illness. What is needed is a shift in emphasis, from seeking to ally an animal model to a specific disorder, to one focused on a more systematic assessment of the neurobiological and behavioural outcomes of any given genetic or environmental manipulation.
Assuntos
Modelos Animais de Doenças , Transtornos Mentais/genética , Camundongos Mutantes/genética , Ratos Mutantes/genética , Animais , Interação Gene-Ambiente , Pleiotropia Genética , Estudo de Associação Genômica Ampla/métodos , Transtornos Mentais/fisiopatologia , Camundongos , Camundongos Mutantes/fisiologia , Polimorfismo Genético , Ratos , Ratos Mutantes/fisiologiaRESUMO
We used a fully automated system for the behavioural measurement of physiologically meaningful properties of basic mechanisms of cognition to test two strains of heterozygous mutant mice, Bfc (batface) and L1, and their wild-type littermate controls. Both of the target genes are involved in the establishment and maintenance of synapses. We find that the Bfc heterozygotes show reduced precision in their representation of interval duration, whereas the L1 heterozygotes show increased precision. These effects are functionally specific, because many other measures made on the same mice are unaffected, namely: the accuracy of matching temporal investment ratios to income ratios in a matching protocol, the rate of instrumental and classical conditioning, the latency to initiate a cued instrumental response, the trials on task and the impulsivity in a switch paradigm, the accuracy with which mice adjust timed switches to changes in the temporal constraints, the days to acquisition, and mean onset time and onset variability in the circadian anticipation of food availability.
Assuntos
Antecipação Psicológica/fisiologia , Adesão Celular/genética , Ritmo Circadiano/fisiologia , Cognição/fisiologia , Camundongos Mutantes/fisiologia , Modelos Biológicos , Percepção do Tempo/fisiologia , Animais , Comportamento Alimentar/fisiologia , Feminino , Heterozigoto , Camundongos , Camundongos Mutantes/genética , Especificidade da EspécieRESUMO
The consortium for functional glycomics (CFG) was a large research initiative providing networking and resources for investigators studying the role of glycans and glycan-binding proteins in health and disease. Starting in 2001, six scientific cores were established to generate data, materials and new technologies. By the end of funding in 2011, the mouse phenotype core (MPC) submitted data to a website from the phenotype screen of 36 mutant mouse strains deficient in a gene for either a glycan-binding protein (GBP) or glycosyltransferase (GT). Each mutant strain was allotted three months for analysis and screened by standard phenotype assays used in the fields of immunology, histology, hematology, coagulation, serum chemistry, metabolism and behavior. Twenty of the deficient mouse strains had been studied in other laboratories, and additional tests were performed on these strains to confirm previous observations and discover new data. The CFG constructed 16 new homozygous mutant mouse strains and completed the initial phenotype screen of the majority of these new mutant strains. In total, >300 phenotype changes were observed, but considering the over 100 assays performed on each strain, most of the phenotypes were unchanged. Phenotype differences include abnormal testis morphology in GlcNAcT9- and Siglec-H-deficient mice and lethality in Pomgnt1-deficient mice. The numerous altered phenotypes discovered, along with the consideration of the significant findings of normality, will provide a platform for future characterization to understand the important roles of glycans and GBPs in the mechanisms of health and disease.
Assuntos
Glicosiltransferases/genética , Lectinas/genética , Camundongos Mutantes/genética , Fenótipo , Animais , Marcação de Genes , Homozigoto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes/anatomia & histologia , Camundongos Mutantes/imunologia , Camundongos Mutantes/fisiologia , MutaçãoRESUMO
OBJECTIVE: The effects of alcohol (ethanol) are well documented and contribute to significant health problems and financial burden on the health care system. Several mouse models have been described that facilitate studies of the effects of alcohol on the mouse immune system. Our goal was to establish a chronic alcohol mouse model using the immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. This severely immunodeficient model has previously been shown to allow efficient engraftment of human hematopoietic repopulating cells and cancer cells, thereby facilitating diverse studies on human hematopoiesis, immune cell function, and oncogenesis in vivo. METHOD: NSG mice were provided ethanol in their drinking water as the only available fluid, starting at 5% weight/volume (w/v) and subsequently were increased to 10%, 15%, and 20% w/v. Mice were then maintained at 20% w/v, a level that models chronic alcohol use in humans. Alcohol consumption and weight were monitored. RESULTS: NSG mice readily consumed alcohol throughout the study and showed no adverse effects. No significant difference between group mean weights was identified the day before increasing the ethanol dose or at the end of 5 weeks at 20% w/v (p > .28). While the mice were maintained at 20% w/v ethanol, the mean daily ethanol intake was 27.2 g/kg of body weight, 32% of caloric intake. CONCLUSIONS: Here we have established a chronic alcohol mouse model using the powerful immunodeficient NSG mouse. This model should allow for novel studies on the effects of alcohol on engrafted human cells, including studies on the effects of alcohol on hematopoiesis, immunity, and cancer.
Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Consumo de Bebidas Alcoólicas/psicologia , Alcoolismo/psicologia , Modelos Animais de Doenças , Camundongos Mutantes/psicologia , Alcoolismo/fisiopatologia , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Ingestão de Energia/efeitos dos fármacos , Ingestão de Energia/fisiologia , Feminino , Camundongos , Camundongos Mutantes/imunologia , Camundongos Mutantes/fisiologiaRESUMO
As part of the RIKEN large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis project, we screened mice with a dominant mutation that exhibited abnormal behavior using an open-field test and a home-cage activity test. We tested 495 male progeny of C57BL/6J males treated with ENU and untreated C3H/HeJ females using the open-field test and isolated behavioral mutant M101736, which exhibited a significant increase in spontaneous locomotor activity. We identified a missense mutation in the Tuba1 gene, which encodes the TUBA1 protein, and designated the mutant gene Tuba1(Rgsc1736). This mutation results in an aspartic acid to glycine substitution in the TUBA1 protein. Detailed analyses revealed that Tuba1(Rgsc1736) heterozygotes exhibited inattention to novel objects and aberrant patterns of home-cage activity. The results of a behavioral pharmacological analysis using methylphenidate and morphological analyses of embryonic and adult brains suggested that Tuba1(Rgsc1736) is a novel animal model for neurodevelopmental disorders.
Assuntos
Comportamento Animal/fisiologia , Camundongos Mutantes/genética , Neocórtex/patologia , Neurônios/patologia , Tubulina (Proteína)/genética , Análise de Variância , Animais , Animais Recém-Nascidos , Ácido Aspártico/genética , Atenção/efeitos dos fármacos , Atenção/fisiologia , Bromodesoxiuridina , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Mapeamento Cromossômico , Análise Mutacional de DNA , Adaptação à Escuridão/efeitos dos fármacos , Adaptação à Escuridão/genética , Deficiências do Desenvolvimento/tratamento farmacológico , Deficiências do Desenvolvimento/genética , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Etilnitrosoureia/farmacologia , Comportamento Exploratório/fisiologia , Feminino , Regulação da Expressão Gênica/genética , Glicina/genética , Comportamento de Retorno ao Território Vital/fisiologia , Masculino , Metilfenidato/farmacologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Mutantes/fisiologia , Microscopia Eletrônica de Transmissão , Mutagênese/efeitos dos fármacos , Mutagênicos/farmacologia , Neocórtex/embriologia , Neocórtex/crescimento & desenvolvimento , Neurônios/ultraestrutura , Fenótipo , Fatores de TempoRESUMO
The mouse, as a genetically defined and easily manipulated model organism, has played a critical role in unraveling the mechanisms of craniofacial development and dysmorphology. While numerous gene knockout strains that display craniofacial abnormalities and essential recombinase tool strains with craniofacial-specific expression have been generated, many are absent from public repositories. Large-scale, international resource-generating initiatives promise to address this concern, providing a comprehensive set of targeted mutations and a suite of new Cre driver strains. In addition, panels of genetically defined strains provide tools to dissect the multigenic, complex nature of craniofacial development, adding to the foundation of information gained from single gene studies. Continued progress will require awareness and access to these essential mouse resources. In this review, current mouse resources, large-scale efforts, and potential future directions will be outlined and discussed.
Assuntos
Anormalidades Craniofaciais/genética , Bases de Dados Factuais , Desenvolvimento Maxilofacial/fisiologia , Camundongos Mutantes/fisiologia , Modelos Animais , Fenótipo , Crânio/embriologia , Animais , Integrases/metabolismo , Cooperação Internacional , Internet , Camundongos , Camundongos Mutantes/genética , Mutação/genética , Crânio/anatomia & histologiaRESUMO
Many proteins have been proposed to act as surrogate markers of organ damage, yet for many candidates the essential biomarker characteristics that link the protein to the injured organ have not yet been described. We generated an Ngal reporter mouse by inserting a double-fusion reporter gene encoding luciferase-2 and mCherry (Luc2-mC) into the Ngal (Lcn2) locus. The Ngal-Luc2-mC reporter accurately recapitulated the endogenous message and illuminated injuries in vivo in real time. In the kidney, Ngal-Luc2-mC imaging showed a sensitive, rapid, dose-dependent, reversible, and organ- and cell-specific relationship with tubular stress, which correlated with the level of urinary Ngal (uNgal). Unexpectedly, specific cells of the distal nephron were the source of uNgal. Cells isolated from Ngal-Luc2-mC mice also revealed both the onset and the resolution of the injury, and the actions of NF-κB inhibitors and antibiotics during infection. Thus, imaging of Ngal-Luc2-mC mice and cells identified injurious and reparative agents that affect kidney damage.
Assuntos
Proteínas de Fase Aguda/fisiologia , Genes Reporter/fisiologia , Rim/lesões , Lipocalinas/fisiologia , Proteínas Oncogênicas/fisiologia , Proteínas de Fase Aguda/genética , Animais , Biomarcadores/sangue , Cisplatino/farmacologia , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Genes Reporter/efeitos dos fármacos , Gentamicinas/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Lipídeo A/farmacologia , Lipocalina-2 , Lipocalinas/sangue , Lipocalinas/genética , Masculino , Camundongos , Camundongos Mutantes/genética , Camundongos Mutantes/fisiologia , Proteínas Oncogênicas/sangue , Proteínas Oncogênicas/genéticaRESUMO
Many mutant mouse strains display pathological behaviors, such as head tilts, head bobbing, or circling and waltzing, strongly suggesting that their vestibular system is impaired. Recently, Yoder and Taube studied head direction signals in tilted mutant mice, which have an impaired gravitation sensitivity in the vestibular periphery. Here we summarize their findings and discuss a caveat related to the general use of mutant mouse strains in systems physiology.
Assuntos
Sensação Gravitacional/fisiologia , Movimentos da Cabeça/fisiologia , Transtornos da Percepção/etiologia , Doenças Vestibulares/complicações , Animais , Camundongos , Camundongos Mutantes/fisiologia , Percepção de Movimento , Transtornos da Percepção/patologia , Células Receptoras Sensoriais/fisiologia , Doenças Vestibulares/genética , Doenças Vestibulares/patologiaRESUMO
A role for nerve growth factor (NGF) in contributing to increased voiding frequency and altered sensation from the urinary bladder has been suggested. Previous studies have examined the expression and regulation of tyrosine kinase receptors (Trks) in micturition reflexes with urinary bladder inflammation. The present studies examine the expression and regulation of another receptor known to bind NGF, p75(NTR), after various durations of bladder inflammation induced by cyclophosphamide (CYP). CYP-induced cystitis increased (P < or = 0.001) p75(NTR) expression in the superficial lateral and medial dorsal horn in L1-L2 and L6-S1 spinal segments. The number of p75(NTR)-immunoreactive (-IR) cells in the lumbosacral dorsal root ganglia (DRG) also increased (P < or = 0.05) with CYP-induced cystitis (acute, intermediate, and chronic). Quantitative, real-time polymerase chain reaction also demonstrated significant increases (P < or = 0.01) in p75(NTR) mRNA in DRG with intermediate and chronic CYP-induced cystitis. Retrograde dye-tracing techniques with Fastblue were used to identify presumptive bladder afferent cells in the lumbosacral DRG. In bladder afferent cells in DRG, p75(NTR)-IR was also increased (P < or = 0.01) with cystitis. In addition to increases in p75(NTR)-IR in DRG cell bodies, increases (P < or = 0.001) in pericellular (encircling DRG cells) p75(NTR)-IR in DRG also increased. Confocal analyses demonstrated that pericellular p75(NTR)-IR was not colocalized with the glial marker, glial fibrillary acidic protein (GFAP). These studies demonstrate that p75(NTR) expression in micturition reflexes is present constitutively and modified by bladder inflammation. The functional significance of p75(NTR) expression in micturition reflexes remains to be determined.
Assuntos
Cistite/fisiopatologia , Camundongos Mutantes/fisiologia , Ratos/fisiologia , Receptores de Fator de Crescimento Neural/metabolismo , Bexiga Urinária/inervação , Animais , Antineoplásicos Alquilantes , Ciclofosfamida , Cistite/induzido quimicamente , Cistite/metabolismo , Modelos Animais de Doenças , Feminino , Gânglios Espinais/citologia , Masculino , Camundongos , Proteínas do Tecido Nervoso , Neurônios Aferentes/metabolismo , Células do Corno Posterior/citologia , Receptores de Fatores de Crescimento , Receptores de Fator de Crescimento Neural/genética , Bexiga Urinária/fisiopatologiaRESUMO
Agouti-related protein (AgRP) is a key orexigenic neuropeptide expressed in the hypothalamic arcuate nucleus and a marker for neurons conveying hormonal signals of hunger to the brain. Mice homozygous for the anorexia (anx) mutation are characterized by decreased food intake, starvation, and death by 3-5 weeks of age. At this stage immunoreactivity for AgRP is increased in cell bodies but decreased in the nerve terminals. We studied when during early postnatal development the aberrant phenotype of the AgRP system becomes apparent in anx/anx mice and possible underlying mechanisms. AgRP and ionized calcium binding adapter molecule (Iba1), a marker for activated microglia, as well as Toll-like receptor 2 (TLR-2), were studied by immunohistochemistry at postnatal days P1, P5, P10, P12, P15 and P21 in anx/anx and wild-type mice. We found that the AgRP system in the anx/anx mouse develops similarly to the wild type until P12, when AgRP fibers in anx/anx mice cease to increase in density in the main projection areas. At P21, AgRP fiber density in anx/anx mice was significantly reduced vs. P15, in certain regions. At P21, many strongly AgRP-positive cell bodies were observed in the anx/anx arcuate nucleus vs. only few and weakly fluorescent ones in the wild type. The decrease in AgRP fiber density in anx/anx mice overlapped with an increase in Iba1 and TLR-2 immunoreactivities. Thus, the aberrant appearance of the AgRP system in the anx/anx mouse in the early postnatal development could involve a microglia-associated process and the innate immune system.
Assuntos
Proteína Relacionada com Agouti/metabolismo , Anorexia/metabolismo , Núcleo Arqueado do Hipotálamo/metabolismo , Camundongos Mutantes/fisiologia , Microglia/metabolismo , Animais , Anticorpos , Núcleo Arqueado do Hipotálamo/imunologia , Núcleo Arqueado do Hipotálamo/patologia , Proteínas de Ligação ao Cálcio/imunologia , Proteínas de Ligação ao Cálcio/metabolismo , Ingestão de Alimentos/fisiologia , Feminino , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos , Proteínas dos Microfilamentos , Microglia/imunologia , Microglia/patologia , Mutação , Degeneração Neural/imunologia , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Neuropeptídeo Y/imunologia , Neuropeptídeo Y/metabolismo , Receptor 2 Toll-Like/imunologia , Receptor 2 Toll-Like/metabolismoRESUMO
Mast cells are the progeny of hematopoietic stem cells. Mutant mice lacking mast cells or possessing abnormal mast cells, such as W/Wv, Sl/Sld, and mi/mi, are useful for investigating the developmental process. Recently, mast cell progenitors were identified with sorting techniques. Recent progress in research into mast cell development is reviewed.
Assuntos
Diferenciação Celular/genética , Mastócitos/fisiologia , Camundongos Mutantes/fisiologia , Animais , Antígenos CD/metabolismo , Diferenciação Celular/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Camundongos , Fenótipo , Fator de Células-Tronco/metabolismoRESUMO
Previous studies of rod photoreceptors in vivo have employed a paired-flash electroretinographic (ERG) technique to determine rod response properties. To test whether absence versus presence of the ERG b-wave affects the photoreceptor response derived by the paired-flash method, we examined paired-flash-derived responses obtained from nob mice, a mutant strain with a defect in signal transduction between photoreceptors and ON bipolar cells that causes a lack of the b-wave. Normal littermates of the nob mice served as controls. The normalized amplitude-intensity relation of the derived response determined in nob mice at the near-peak time of 86 ms was similar to that determined for the controls. The full time course of the derived rod response was obtained for test flash strengths ranging from 0.11 to 17.38 scotopic cd s m(-2) (sc cd s m(-2)). Time-course data obtained from nob and control mice exhibited significant but generally modest differences. With saturating test flash strengths, half-recovery times for the derived response of nob versus control mice differed by approximately 60 ms or less about the combined (nob and control) average respective values. Time course data also were obtained before versus after intravitreal injection of L-2-amino-4-phosphonobutyrate (APB) (which blocks transmission from photoreceptors to depolarizing bipolar cells) and of cis 2,3-piperidine dicarboxylic acid (PDA) (which blocks transmission to OFF bipolar cells, and to horizontal, amacrine and ganglion cells). Neither APB nor PDA substantially affected derived responses obtained from nob or control mice. The results provide quantitative information on the effect of b-wave removal on the paired-flash-derived response in mouse. They argue against a substantial skewing effect of the b-wave on the paired-flash-derived response obtained in normal mice and are consistent with the notion that, to good approximation, this derived response represents the isolated flash response of the photoreceptors in both nob and normal mice.
Assuntos
Eletrorretinografia , Camundongos Mutantes/fisiologia , Células Fotorreceptoras Retinianas Bastonetes/fisiologia , Algoritmos , Aminobutiratos/farmacologia , Animais , Relação Dose-Resposta à Radiação , Eletrorretinografia/efeitos dos fármacos , Eletrorretinografia/efeitos da radiação , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Iluminação , Masculino , Camundongos , Estimulação Luminosa/métodos , Ácidos Pipecólicos/farmacologia , Proteoglicanas/genética , Células Fotorreceptoras Retinianas Bastonetes/efeitos dos fármacos , Células Fotorreceptoras Retinianas Bastonetes/efeitos da radiação , Fatores de TempoRESUMO
To support the role of DISC1 in human psychiatric disorders, we identified and analyzed two independently derived ENU-induced mutations in Exon 2 of mouse Disc1. Mice with mutation Q31L showed depressive-like behavior with deficits in the forced swim test and other measures that were reversed by the antidepressant bupropion, but not by rolipram, a phosphodiesterase-4 (PDE4) inhibitor. In contrast, L100P mutant mice exhibited schizophrenic-like behavior, with profound deficits in prepulse inhibition and latent inhibition that were reversed by antipsychotic treatment. Both mutant DISC1 proteins exhibited reduced binding to the known DISC1 binding partner PDE4B. Q31L mutants had lower PDE4B activity, consistent with their resistance to rolipram, suggesting decreased PDE4 activity as a contributory factor in depression. This study demonstrates that Disc1 missense mutations in mice give rise to phenotypes related to depression and schizophrenia, thus supporting the role of DISC1 in major mental illness.
Assuntos
Comportamento Animal/fisiologia , Camundongos Mutantes/fisiologia , Mutação de Sentido Incorreto/genética , Proteínas do Tecido Nervoso/genética , Fenótipo , 3',5'-AMP Cíclico Fosfodiesterases/metabolismo , Alanina/genética , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/anatomia & histologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Análise Mutacional de DNA/métodos , Feminino , Glutamina/genética , Humanos , Leucina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes/anatomia & histologia , Inibição Neural/genética , Ligação Proteica/genética , Reflexo Acústico/genética , Frações Subcelulares/metabolismo , Treonina/genéticaRESUMO
We sought to identify associations of basal metabolic rate (BMR) with morphological traits in laboratory mice. In order to expand the body mass (BM) range at the intra-strain level, and to minimize relevant genetic variation, we used male and female wild type mice (C3HeB/FeJ) and previously unpublished ENU-induced dwarf mutant littermates (David mice), covering a body mass range from 13.5 g through 32.3 g. BMR was measured at 30 degrees C, mice were killed by means of CO(2 )overdose, and body composition (fat mass and lean mass) was subsequently analyzed by dual X-ray absorptiometry (DEXA), after which mice were dissected into 12 (males) and 10 (females) components, respectively. Across the 44 individuals, 43% of the variation in the basal rates of metabolism was associated with BM. The latter explained 47% to 98% of the variability in morphology of the different tissues. Our results demonstrate that sex is a major determinant of body composition and BMR in mice: when adjusted for BM, females contained many larger organs, more fat mass, and less lean mass compared to males. This could be associated with a higher mass adjusted BMR in females. Once the dominant effects of sex and BM on BMR and tissue mass were removed, and after accounting for multiple comparisons, no further significant association between individual variation in BMR and tissue mass emerged.
Assuntos
Metabolismo Basal/fisiologia , Composição Corporal/fisiologia , Índice de Massa Corporal , Nanismo/fisiopatologia , Camundongos Mutantes/fisiologia , Animais , Metabolismo Basal/genética , Composição Corporal/genética , Tamanho Corporal/genética , Tamanho Corporal/fisiologia , Nanismo/genética , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C3H , Tamanho do Órgão/genética , Tamanho do Órgão/fisiologia , FenótipoRESUMO
Transgenic mice are often used to study the physiologic role of a known gene. The design of experiments with transgenic mice usually does not take into account strain and sex differences, at least in isolated vessels. Therefore, we have compared the contractile response of isolated aortae and isolated pulmonary arteries of male and female mice of different strains (CD1, BL6, and DBA). Contractile stimulation was achieved by depolarization due to KCl, alpha1-adrenoceptor stimulation by phenylephrine and inhibition of protein phosphatase activity by cantharidin. In isolated aorta, strain-specific differences in contractility and sex-specific differences could be observed. The concentration of phenylephrine (PE) inducing half maximal contraction (EC50) was different between aortae from DBA male mice and the other strains tested. Phasic contractions of isolated aortic rings due to PE were seen in all mice except DBA male. In isolated pulmonary arteries, strain-specific differences and sex-specific differences could be observed. The EC50-values of PE were not different between all groups. Phasic contractions due to PE were only seen in pulmonary arteries from CD1 male and BL6 female. In conclusion, strain- and sex-specific differences should be considered in selecting mice used for transgenesis or gene targeting experiments.
Assuntos
Aorta Torácica/efeitos dos fármacos , Camundongos Endogâmicos/fisiologia , Camundongos Mutantes/fisiologia , Artéria Pulmonar/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Agonistas alfa-Adrenérgicos/farmacologia , Animais , Aorta Torácica/fisiologia , Cantaridina/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos DBA , Camundongos Endogâmicos/anatomia & histologia , Camundongos Mutantes/anatomia & histologia , Fenilefrina/farmacologia , Potássio/farmacologia , Cloreto de Potássio/farmacologia , Artéria Pulmonar/fisiologia , Fatores Sexuais , Especificidade da Espécie , Fatores de TempoRESUMO
Mutations in the human ALMS1 gene are responsible for Alström syndrome, a disorder in which key metabolic and endocrinological features include childhood-onset obesity, metabolic syndrome, and diabetes, as well as infertility. ALMS1 localizes to the basal bodies of cilia and plays a role in intracellular trafficking, but the biological functions of ALMS1 and how these relate to the pathogenesis of obesity, diabetes, and infertility remain unclear. Here we describe a new mouse model of Alström syndrome, fat aussie, caused by a spontaneous mutation in the Alms1 gene. Fat aussie (Alms1 foz/foz) mice are of normal weight when young but, by 120 d of age, they become obese and hyperinsulinemic. Diabetes develops in Alms1 foz/foz mice accompanied by pancreatic islet hyperplasia and islet cysts. Female mice are fertile before the onset of obesity and metabolic syndrome; however, male fat aussie mice are sterile due to a progressive germ cell loss followed by an almost complete block of development at the round-to-elongating spermatid stage of spermatogenesis. In conclusion, Alms1 foz/foz mouse is a new animal model in which to study the pathogenesis of the metabolic and fertility defects of Alström syndrome, including the role of ALMS1 in appetite regulation, pathogenesis of the metabolic syndrome, pancreatic islet physiology, and spermatogenesis.
Assuntos
Proteínas de Ligação a DNA/fisiologia , Diabetes Mellitus Experimental/genética , Camundongos Mutantes/genética , Modelos Animais , Obesidade/genética , Espermatogênese/genética , Animais , Sequência de Bases , Composição Corporal , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA/genética , Ingestão de Alimentos , Feminino , Mutação da Fase de Leitura , Infertilidade Masculina/patologia , Masculino , Camundongos , Camundongos Mutantes/metabolismo , Camundongos Mutantes/fisiologia , Dados de Sequência Molecular , Espermatogênese/fisiologia , SíndromeRESUMO
Human vestibular dysfunction is an increasing clinical problem. Degeneration or displacement of otoconia is a significant etiology of age-related balance disorders and Benign Positional Vertigo (BPV). In addition, commonly used antibiotics, such as aminoglycoside antibiotics, can lead to disruption of otoconial structure and function. Despite such clinical significance, relatively little information has been compiled about the development and maintenance of otoconia in humans. Recent studies in model organisms and other mammalian organ systems have revealed some of the proteins and processes required for the normal biomineralization of otoconia and otoliths in the inner ear of vertebrates. Orchestration of extracellular biomineralization requires bringing together ionic and proteinaceous components in time and space. Coordination of these events requires the normal formation of the otocyst and sensory maculae, specific secretion and localization of extracellular matrix proteins, as well as tight regulation of the endolymph ionic environment. Disruption of any of these processes can lead to the formation of abnormally shaped, or ectopic, otoconia, or otoconial agenesis. We propose that normal generation of otoconia requires a complex temporal and spatial control of developmental and biochemical events. In this review, we suggest a new hypothetical model for normal otoconial and otolith formation based on matrix vesicle mineralization in bone which we believe to be supported by information from existing mutants, morphants, and biochemical studies.