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1.
Mouse knockout of guanylyl cyclase C: Recognition memory deficits in the absence of activity changes
Elizabeth A. Mann Chiho Sugimoto Michael T. Williams Charles V. Vorhees 《Genes, Brain & Behavior》2019,18(5)
Guanylyl cyclase C (GC‐C) is found in brain regions where dopamine is expressed. We characterized a mouse in which GC‐C was knocked out (KO) that was reported to be a model of attention deficit hyperactivity disorder (ADHD). We re‐examined this model and controlled for litter effects, used 16 to 23 mice per genotype per sex and assessed an array of behavioral and neurochemical outcomes. GC‐C KO mice showed no phenotypic differences from wild‐type mice on most behavioral tests, or on striatal or hippocampal monoamines, and notably no evidence of an ADHD‐like phenotype. KO mice were impaired on novel object recognition, had decreased tactile startle but not acoustic startle, and females had increased latency on cued training trials in the Morris water maze, but not hidden platform spatial learning trials. Open‐field activity showed small differences in females but not males. The data indicate that the GC‐C KO mouse with proper controls and sample sizes has a moderate cognitive and startle phenotype but has no ADHD‐like phenotype. 相似文献
2.
X-linked retinoschisis (XLRS) is an inherited form of macular degeneration that is caused by mutations in the retinoschisin (RS1) gene. In addition to macular degeneration, other major characteristics of XLRS include splitting of the retina (schisis) and impaired synaptic transmission as indicated by a reduction in the electroretinogram b-wave. It has been known that patients carrying RS1 mutations show a broad range of phenotypic variability. Interestingly, phenotypic variation is observed even among family members with the same RS1 mutation, suggesting the existence of genetic or environmental factors that contribute to the severity of XLRS. However, in the human population, the cause of phenotypic variability and the contribution of genetic modifiers for this relatively rare disease are difficult to study and poorly understood. In this study, using a mouse model for XLRS, we show that genetic factors can contribute to the severity of the retinoschisis phenotype. We report evidence of a major genetic modifier of Rs1, which affects the disease severity in these animals. A quantitative trait locus (QTL), named modifier of Rs1 1 (Mor1), is mapped on chromosome (Chr) 7. When homozygous, the Mor1 allele from the inbred mouse strain AKR/J diminishes the severity of the schisis phenotype in Rs1(tmgc1)/Y male and Rs1(tmgc1)/Rs1(tmgc1) female mice. We also show that the penetrance of the disease phenotype is affected by additional genetic factor(s). Our study suggests that multiple genetic modifiers could potentially be responsible for the phenotypic variation in human XLRS. 相似文献
3.
The mouse N-ethyl-N-nitrosourea (ENU) mutagenesis program at the Genomics Institute of the Novartis Research Foundation (GNF) uses MouseTRACS
to analyze phenotype screens and manage animal husbandry. MouseTRACS is a Web-based laboratory informatics system that electronically
records and organizes mouse colony operations, prints cage cards, tracks inventory, manages requests, and reports Institutional
Animal Care and Use Committee (IACUC) protocol usage. For efficient phenotype screening, MouseTRACS identifies mutants, visualizes
data, and maps mutations. It displays and integrates phenotype and genotype data using likelihood odds ratio (LOD) plots of
genetic linkage between genotype and phenotype. More detailed mapping intervals show individual single nucleotide polymorphism
(SNP) markers in the context of phenotype. In addition, dynamically generated pedigree diagrams and inventory reports linked
to screening results summarize the inheritance pattern and the degree of penetrance. MouseTRACS displays screening data in
tables and uses standard charts such as box plots, histograms, scatter plots, and customized charts looking at clustered mice
or cross pedigree comparisons. In summary, MouseTRACS enables the efficient screening, analysis, and management of thousands
of animals to find mutant mice and identify novel gene functions. MouseTRACS is available under an open source license at
.
Electronic Supplementary Material Electronic Supplementary material is available for this article at
and accessible for authorised users. 相似文献
4.
Non-imprinted Igf2r expression decreases growth and rescues the Tme mutation in mice 总被引:7,自引:0,他引:7
Wutz A Theussl HC Dausman J Jaenisch R Barlow DP Wagner EF 《Development (Cambridge, England)》2001,128(10):1881-1887
In the mouse the insulin-like growth factor receptor type 2 gene (Igf2r) is imprinted and maternally expressed. Igf2r encodes a trans-membrane receptor that transports mannose-6-phosphate tagged proteins and insulin-like growth factor 2 to lysosomes. During development the receptor reduces the amount of insulin-like growth factors and thereby decreases embryonic growth. The dosage of the gene is tightly regulated by genomic imprinting, leaving only the maternal copy of the gene active. Although the function of Igf2r in development is well established, the function of imprinting the gene remains elusive. Gene targeting experiments in mouse have demonstrated that the majority of genes are not sensitive to gene dosage, and mice heterozygous for mutations generally lack phenotypic alterations. To investigate whether reduction of Igf2r gene dosage by genomic imprinting has functional consequences for development we generated a non-imprinted allele (R2Delta). We restored biallelic expression to Igf2r by deleting a critical element for repression of the paternal allele (region 2) in mouse embryonic stem cells. Maternal inheritance of the R2Delta allele has no phenotype; however, paternal inheritance results in biallelic expression of Igf2r, which causes a 20% reduction in weight late in embryonic development that persists into adulthood. Paternal inheritance of the R2Delta allele rescues the lethality of a maternally inherited Igf2r null allele and a maternally inherited Tme (T-associated maternal effect) mutation. These data show that the biological function of imprinting Igf2r is to increase birth weight and they also establish Igf2r as the Tme gene. 相似文献
5.
What determines phenotype is one of the most fundamental questions in biology. Historically, the search for answers had focused on genetic or environmental variants, but recent studies in epigenetics have revealed a third mechanism that can influence phenotypic outcomes, even in the absence of genetic or environmental heterogeneity. Even more surprisingly, some epigenetic variants, or epialleles, can be inherited by the offspring, indicating the existence of a mechanism for biological heredity that is not based on DNA sequence. Recent work from mouse models, human monozygotic twin studies, and large-scale epigenetic profiling suggests that epigenetically determined phenotypes and epigenetic inheritance are more common than previously appreciated. 相似文献
6.
Feldman MD Mao Y Valvano JW Pearce JA Freeman GL 《American journal of physiology. Heart and circulatory physiology》2000,279(3):H1411-H1420
Transgenic mice offer a valuable way to relate gene products to phenotype, but the ability to assess the cardiovascular phenotype with pressure-volume analysis has lagged. Conductance measurement offers a method to generate an instantaneous left ventricular (LV) volume signal in the mouse but has been limited by the volume signal being a combination of blood and LV muscle. We hypothesized that by developing a mouse conductance system that operates at several simultaneous frequencies, we could identify and correct for the myocardial contribution to the instantaneous volume signal. This hypothesis is based on the assumption that mouse myocardial conductivity will vary with frequency, whereas mouse blood conductivity will not. Consistent with this hypothesis, we demonstrated that at higher excitation frequency, greater end-diastolic and end-systolic conductance are detected, as well as a smaller difference between the two. We then empirically solved for LV blood volume using two frequencies. We combined measured resistivity of mouse myocardium with an analytic approach and extracted an estimate of LV blood volume from the raw conductance signal. Development of a multifrequency catheter-based system to determine LV function could be a tool to assess cardiovascular phenotype in transgenic mice. 相似文献
8.
Fiona C Mansergh Timothy Wells Carole Elford Samuel L Evans Mark J Perry Martin J Evans Bronwen A J Evans 《Physiological genomics》2007,32(1):64-73
Sparc null mutants have been generated independently via targeted mutations in exons 4 and 6. Previous studies have identified low-turnover osteopenia in the 129Sv/C57BL/6 exon 4 knockout. Since both Sparc null mutations result in complete absence of Sparc protein, similar phenotypic outcomes are likely. However, genetic background (strain) and/or linkage disequilibrium effects can influence phenotype. Different inactivating mutations should be tested in various mouse strains; similar phenotypic outcomes can then confidently be assigned to the mutated gene. We have evaluated the bone phenotype in the 129Sv/EvSparc(tm1cam) exon 6 knockout at 4 and 9 mo, using physical measurement, mechanical strength tests, and DXA scanning. We have also quantified bone marrow adiposity and circulating leptin levels to assess adipose tissue metabolism. 129Sv/EvSparc(tm1cam) null mice show decreased bone mineral density and bone mineral content and increased mechanical fragility of bone, in line with previous studies. Differences were also noted. Increased body weight and levels of bone marrow adiposity but decreased circulating leptin concentrations were identified at 4, but not 9 mo, and 129Sv/EvSparc(tm1cam) null mice also had shorter femurs. Molecular phenotyping was carried out using mouse HGMP NIA microarrays with cortical femur samples at various ages, using semiquantitative RT-PCR validation. We identified 429 genes highly expressed in normal bone. Six genes (Sparc, Zfp162, Bysl, E2F4, two ESTs) are differentially regulated in 129Sv/EvSparc(tm1cam) cortical femur vs. 129Sv/Ev controls. We confirm low-turnover osteopenia as a feature of the Sparc null phenotype, identifying the usefulness of this mouse as a model for human osteoporosis. 相似文献
9.
The use of 129 strain-derived embryonic stem cell lines for targeted gene mutation in mice has led directly to an expanded use of this inbred strain worldwide. It has been noted, however, that the 129 genetic background can make a significant contribution to the severity of a mutant phenotype. In this study, we reveal a specific defect in the IL-5 and Rp105 responses of B lymphocytes from two widely used 129 mouse substrains. The response to stimulation through surface IgM is also diminished, although to a lesser degree, in these mice. The lesion appears to reduce significantly the expression of the alpha-chain of the IL-5R, but may also influence events downstream of the IL-5R. This phenotype displays a codominant inheritance pattern, and is accompanied by a variable but significant depression of peritoneal B-1 cell numbers in 50% of the mice. 相似文献
10.
Adam J.W. Paige Brent W. Kiernan Anabel Varela Michael J.C. Rogers David Hughes Karen P. Steel Steve D.M. Brown 《Mammalian genome》2000,11(1):51-57
Whirler (wi) mice display profound deafness and a head-tossing and circling phenotype, showing an autosomal recessive mode of inheritance.
The wi mutation has been shown to map close to the Orm gene cluster on mouse Chromosome (Chr) 4. We have, therefore, investigated the Orm loci as candidates for the whirler gene. Detailed mapping and analysis of the Orm gene cluster in both normal and whirler mice indicates the presence of a <48-kb deletion in whirler mice that disrupts the
Orm1 locus. The Orm1 locus is also deleted in the CE/J mouse strain, and we discuss the candidature of Orm1 for the whirler gene.
Received: 22 June 1999 / Accepted: 17 September 1999 相似文献
11.
Berthold Hocher Hannah Haumann Jan Rahnenführer Christoph Reichetzeder Philipp Kalk Thiemo Pfab 《Epigenetics》2016,11(7):539-552
Maternal environmental factors can impact on the phenotype of the offspring via the induction of epigenetic adaptive mechanisms. The advanced fetal programming hypothesis proposes that maternal genetic variants may influence the offspring's phenotype indirectly via epigenetic modification, despite the absence of a primary genetic defect. To test this hypothesis, heterozygous female eNOS knockout mice and wild type mice were bred with male wild type mice. We then assessed the impact of maternal eNOS deficiency on the liver phenotype of wild type offspring. Birth weight of male wild type offspring born to female heterozygous eNOS knockout mice was reduced compared to offspring of wild type mice. Moreover, the offspring displayed a sex specific liver phenotype, with an increased liver weight, due to steatosis. This was accompanied by sex specific differences in expression and DNA methylation of distinct genes. Liver global DNA methylation was significantly enhanced in both male and female offspring. Also, hepatic parameters of carbohydrate metabolism were reduced in male and female offspring. In addition, male mice displayed reductions in various amino acids in the liver. Maternal genetic alterations, such as partial deletion of the eNOS gene, can affect liver metabolism of wild type offspring without transmission of the intrinsic defect. This occurs in a sex specific way, with more detrimental effects in females. This finding demonstrates that a maternal genetic defect can epigenetically alter the phenotype of the offspring, without inheritance of the defect itself. Importantly, these acquired epigenetic phenotypic changes can persist into adulthood. 相似文献
12.
Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment 总被引:35,自引:2,他引:33
Derek C. Rogers E.M.C. Fisher S.D.M. Brown J. Peters A.J. Hunter J.E. Martin 《Mammalian genome》1997,8(10):711-713
For an understanding of the aberrant biology seen in mouse mutations and identification of more subtle phenotype variation,
there is a need for a full clinical and pathological characterization of the animals. Although there has been some use of
sophisticated techniques, the majority of behavioral and functional analyses in mice have been qualitative rather than quantitative
in nature. There is, however, no comprehensive routine screening and testing protocol designed to identify and characterize
phenotype variation or disorders associated with the mouse genome. We have developed the SHIRPA procedure to characterize
the phenotype of mice in three stages. The primary screen utilizes standard methods to provide a behavioral and functional
profile by observational assessment. The secondary screen involves a comprehensive behavioral assessment battery and pathological
analysis. These protocols provide the framework for a general phenotype assessment that is suitable for a wide range of applications,
including the characterization of spontaneous and induced mutants, the analysis of transgenic and gene-targeted phenotypes,
and the definition of variation between strains. The tertiary screening stage described is tailored to the assessment of existing
or potential models of neurological disease, as well as the assessment of phenotypic variability that may be the result of
unknown genetic influences. SHIRPA utilizes standardized protocols for behavioral and functional assessment that provide a
sensitive measure for quantifying phenotype expression in the mouse. These paradigms can be refined to test the function of
specific neural pathways, which will, in turn, contribute to a greater understanding of neurological disorders.
Received: 3 March 1997 / Accepted: 30 May 1997 相似文献
13.
14.
The paper deals with the following question: when do the phenotypic evolutionarily stable state (ESS) and the evolutionarily stable allele distribution (ESAD) coincide? It is supposed that for a sexual population, in dominant-recessive inheritance system, n allele at one autosomal locus determine n possible pure individual phenotypes and each pure phenotype is obtained as the phenotype of a homozygote. Under these conditions, earlier results of the authors imply that, if a phenotype distribution is an ESS then the allele distribution generating it is an ESAD. In this paper, apart from a certain degenerate pay-off matrices, the inverse statement is also proved: if a distribution is an ESAD then the corresponding phenotypic distribution is an ESS. 相似文献
15.
Bruce M. Cattanach 《Molecular & general genetics : MGG》1965,96(3):275-284
Summary The exceptional inheritance of a morphological and behavioural mutant in the mouse is described. Breeding tests demonstrated that two factors are in volved, one of which causes the mutant phenotype while the other suppresses it. It was argued from the combined genetical and cytological data that the two factors are the two rearranged parts of a chromosome translocation, both unbalanced products of which are viable and one giving rise to the mutant phenotype.With 4 Figures in the Text 相似文献
16.
Mouse phenome research: implications of genetic background 总被引:4,自引:0,他引:4
Yoshiki A Moriwaki K 《ILAR journal / National Research Council, Institute of Laboratory Animal Resources》2006,47(2):94-102
Now that sequencing of the mouse genome has been completed, the function of each gene remains to be elucidated through phenotypic analysis. The "genetic background" (in which each gene functions) is defined as the genotype of all other related genes that may interact with the gene of interest, and therefore potentially influences the specific phenotype. To understand the nature and importance of genetic background on phenotypic expression of specific genes, it is necessary to know the origin and evolutionary history of the laboratory mouse genome. Molecular analysis has indicated that the fancy mice of Japan and Europe contributed significantly to the origin of today's laboratory mice. The genetic background of present-day laboratory mice varies by mouse strain, but is mainly derived from the European domesticus subspecies group and to a lesser degree from Asian mice, probably Japanese fancy mice, which belong to the musculus subspecies group. Inbred laboratory mouse strains are genetically uniform due to extensive inbreeding, and they have greatly contributed to the genetic analysis of many Mendelian traits. Meanwhile, for a variety of practical reasons, many transgenic and targeted mutant mice have been created in mice of mixed genetic backgrounds to elucidate the function of the genes, although efforts have been made to create inbred transgenic mice and targeted mutant mice with coisogenic embryonic stem cell lines. Inbred mouse strains have provided uniform genetic background for accurate evaluation of specific genes phenotypes, thus eliminating the phenotypic variations caused by mixed genetic backgrounds. However, the process of inbreeding and selection of various inbred strain characteristics has resulted in inadvertent selection of other undesirable genetic characteristics and mutations that may influence the genotype and preclude effective phenotypic analysis. Because many of the common inbred mouse stains have been established from relatively small gene pools, common inbred strains have limitations in their genetic polymorphisms and phenotypic variations. Wild-derived mouse strains can complement deficiencies of common inbred mouse strains, providing novel allelic variants and phenotypes. Although wild-derived strains are not as tame as the common laboratory strains, their genetic characteristics are attractive for the future study of gene function. 相似文献
17.
Masuya H Yoshikawa S Heida N Toyoda T Wakana S Shiroishi T 《Journal of bioinformatics and computational biology》2007,5(6):1173-1191
Recently, a number of collaborative large-scale mouse mutagenesis programs have been launched. These programs aim for a better understanding of the roles of all individual coding genes and the biological systems in which these genes participate. In international efforts to share phenotypic data among facilities/institutes, it is desirable to integrate information obtained from different phenotypic platforms reliably. Since the definitions of specific phenotypes often depend on a tacit understanding of concepts that tends to vary among different facilities, it is necessary to define phenotypes based on the explicit evidence of assay results. We have developed a website termed PhenoSITE (Phenome Semantics Information with Terminology of Experiments: http://www.gsc.riken.jp/Mouse/), in which we are trying to integrate phenotype-related information using an experimental-evidence-based approach. The site's features include (1) a baseline database for our phenotyping platform; (2) an ontology associating international phenotypic definitions with experimental terminologies used in our phenotyping platform; (3) a database for standardized operation procedures of the phenotyping platform; and (4) a database for mouse mutants using data produced from the large-scale mutagenesis program at RIKEN GSC. We have developed two types of integrated viewers to enhance the accessibility to mutant resource information. One viewer depicts a matrix view of the ontology-based classification and chromosomal location of each gene; the other depicts ontology-mediated integration of experimental protocols, baseline data, and mutant information. These approaches rely entirely upon experiment-based evidence, ensuring the reliability of the integrated data from different phenotyping platforms. 相似文献
18.
The study of mouse models is crucial for the functional annotation of the human genome. The recent improvements in mouse genetics now moved the bottleneck in mouse functional genomics from the generation of mutant mice lines to the phenotypic analysis of these mice lines. Simple, validated, and reproducible phenotyping tests are a prerequisite to improving this phenotyping bottleneck. We analyzed here the impact of simple variations in animal handling and housing procedures, such as cage density, diet, gender, length of fasting, as well as site (retro-orbital vs. tail), timing, and anesthesia used during venipuncture, on biochemical, hematological, and metabolic/endocrine parameters in adult C57BL/6J mice. Our results, which show that minor changes in procedures can profoundly affect biological variables, underscore the importance of establishing uniform and validated animal procedures to improve reproducibility of mouse phenotypic data. 相似文献
19.
Sharma S Stumpo DJ Balajee AS Bock CB Lansdorp PM Brosh RM Blackshear PJ 《Molecular and cellular biology》2007,27(5):1784-1794
The mouse gene Recql is a member of the RecQ subfamily of DEx-H-containing DNA helicases. Five members of this family have been identified in both humans and mice, and mutations in three of these, BLM, WRN, and RECQL4, are associated with human diseases and a cellular phenotype that includes genomic instability. To date, no human disease has been associated with mutations in RECQL and no cellular phenotype has been associated with its deficiency. To gain insight into the physiological function of RECQL, we disrupted Recql in mice. RECQL-deficient mice did not exhibit any apparent phenotypic differences compared to wild-type mice. Cytogenetic analyses of embryonic fibroblasts from the RECQL-deficient mice revealed aneuploidy, spontaneous chromosomal breakage, and frequent translocation events. In addition, the RECQL-deficient cells were hypersensitive to ionizing radiation, exhibited an increased load of DNA damage, and displayed elevated spontaneous sister chromatid exchanges. These results provide evidence that RECQL has a unique cellular role in the DNA repair processes required for genomic integrity. Genetic background, functional redundancy, and perhaps other factors may protect the unstressed mouse from the types of abnormalities that might be expected from the severe chromosomal aberrations detected at the cellular level. 相似文献