Biomedical subjects

Muriel T Davisson

Publications and source records attributed to Muriel T Davisson.

At least 19 recordsLinked to original sources

PubMed2006

Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration.

Misfolded proteins are associated with several pathological conditions including neurodegeneration. Although some of these abnormally folded proteins result from mutations in genes encoding disease-associated proteins (for example, repeat-expansion diseases), more general mechanisms that lead to misfolded proteins in neurons remain largely unknown. Here we demonstrate that low levels of mischarged transfer RNAs (tRNAs) can lead to an intracellular accumulation of misfolded proteins in neurons. These accumulations are accompanied by upregulation of cytoplasmic protein chaperones and by induction of the unfolded protein response. We report that the mouse sticky mutation, which causes cerebellar Purkinje cell loss and ataxia, is a missense mutation in the editing domain of the alanyl-tRNA synthetase gene that compromises the proofreading activity of this enzyme during aminoacylation of tRNAs. These findings demonstrate that disruption of translational fidelity in terminally differentiated neurons leads to the accumulation of misfolded proteins and cell death, and provide a novel mechanism underlying neurodegeneration.

Acetylation↗

PubMed2006

A-to-I pre-mRNA editing of the serotonin 2C receptor: comparisons among inbred mouse strains.

The serotonin receptor 5HT2CR pre-mRNA is subject to adenosine deamination (RNA editing) at five residues located within a 15 nucleotide stretch of the coding region. Such changes of adenosine to inosine (A-to-I) can produce 32 mRNA variants, encoding 24 different protein isoforms, some of which vary in biochemical and pharmacological properties. Because serotonin mediates diverse neurological processes relevant to behavior and because inbred mouse strains vary in their responses to tests of learning and behavior, we have examined the A-to-I editing patterns of the 5HT2CR mRNA in whole brains from eight mouse strains. By sequencing approximately 100 clones from individual mice, we generated detailed information on levels of editing at each site and patterns of editing that identify a total of 28 mRNA and 20 protein isoforms. Significant differences between individuals from different strains were found in total editing frequency, in the proportion of transcripts with 1 and 4 edited sites, in editing frequency at the A, B, E and D sites, in amino acid frequencies at positions 157 and 161, and in subsets of major protein isoforms. Primer extension assays were used to show that individuals within strains (six C3H.B-+rd1 and four 129SvImrJ) displayed no significant differences in any feature. These findings suggest that genetic background contributes to subtle variation in 5HT2CR mRNA editing patterns which may have consequences for pharmacological treatments and behavioral testing.

Adenosine↗

PubMed2006

Strategies for managing an ever increasing mutant mouse repository.

Over 10,000 mouse strains and more than 20,000 mouse ES cells containing gene-trapped or targeted mutations are available to researchers. The mouse strains and stocks include those with spontaneous, genetically engineered and induced mutations, as well as 100s of inbred strains and strain panels, valuable for quantitative trait locus (QTL) and modifier gene identification. Current worldwide initiatives are expected to result in multiple mutations in every mouse gene in the first 10 years of the 21st century. Managing the rapid and cost effective distribution of these burgeoning resources to scientists around the world will be challenging for scientists and mouse repositories. Here we describe new strategies for managing and distributing mice.

Animals↗

PubMed2006

Mutations in the gene encoding the low-density lipoprotein receptor LRP4 cause abnormal limb development in the mouse.

Positional cloning of two recessive mutations of the mouse that cause polysyndactyly (dan and mdig-Chr 2) confirmed that the gene encoding MEGF7/LRP4, a member of the low-density lipoprotein receptor family, plays an essential role in the process of digit differentiation. Pathologies observed in the mutant mice provide insight into understanding the function(s) of LRP4 as a negative regulator of the Wnt-beta-catenin signaling pathway and may help identify the genetic basis for common human disorders with similar phenotypes.

Animals↗

PubMed2005

Trak1 mutation disrupts GABA(A) receptor homeostasis in hypertonic mice.

Hypertonia, which results from motor pathway defects in the central nervous system (CNS), is observed in numerous neurological conditions, including cerebral palsy, stroke, spinal cord injury, stiff-person syndrome, spastic paraplegia, dystonia and Parkinson disease. Mice with mutation in the hypertonic (hyrt) gene exhibit severe hypertonia as their primary symptom. Here we show that hyrt mutant mice have much lower levels of gamma-aminobutyric acid type A (GABA(A)) receptors in their CNS, particularly the lower motor neurons, than do wild-type mice, indicating that the hypertonicity of the mutants is likely to be caused by deficits in GABA-mediated motor neuron inhibition. We cloned the responsible gene, trafficking protein, kinesin binding 1 (Trak1), and showed that its protein product interacts with GABA(A) receptors. Our data implicate Trak1 as a crucial regulator of GABA(A) receptor homeostasis and underscore the importance of hyrt mice as a model for studying the molecular etiology of hypertonia associated with human neurological diseases.

Adaptor Proteins, Vesicular Transport↗

PubMed2005

Chromosomal inversion discovered in C3H/HeJ mice.

Mice of the inbred mouse strain C3H/HeJ have been shown to be homozygous for a chromosomal inversion on Chromosome (Chr) 6. The inversion encompasses about 20% of the chromosome from approximately 73 Mb to approximately 116 Mb. The importance of this finding is that linkage crosses using C3H/HeJ will show no recombination in this region of Chr 6. The inversion has no apparent effect on the phenotype of C3H/HeJ mice and its presence should not affect biological studies; however, use of C3H/HeJ mice for genetic analysis of Chr 6 should be avoided or the results interpreted with the inversion in mind. The inversion has been named In(6)1J (inversion Chr 6, Jackson 1).

Animals↗

PubMed2005

Behavioral, cognitive and biochemical responses to different environmental conditions in male Ts65Dn mice, a model of Down syndrome.

Ts65Dn mouse is the most widely accepted model for Down syndrome. We previously showed that environmental enrichment improved spatial learning in female but deteriorated it in male Ts65Dn mice. This study analyzed the factors contributing to the disturbed cognition of male Ts65Dn mice after enriched housing, by allocating male control and Ts65Dn mice in four conditions after weaning: small (n = 2-3) and large group (n = 8-10) housing, and enriched housing in small (2-3) and large groups (8-10). Learning, aggressive behavior, anxiety-like behavior and biochemical correlates of stress were evaluated when Ts65Dn and control mice were 4-5 months old. Environmental enrichment in large mixed colonies of Ts65Dn and diploid littermates disturbed behavioral and learning skills of Ts65Dn mice in the Morris water maze. ACTH and testosterone levels were not modified in any group of mice. Ts65Dn and control mice subjected to enriched housing in large groups and Ts65Dn mice housed in large groups showed higher corticosterone levels. Aggressive behavior was evaluated by measuring the number of attacks performed in the presence of an intruder. Ts65Dn mice performed less attacks than controls in all conditions, especially after enriched housing, indicating subordination. In the plus maze, cognitive aspects (i.e. risk assessment) and motor components (open arm avoidance) of anxiety behavior were evaluated; no difference in any condition was found. It is suggested that an excess of social and/or physical stimulation in Ts65Dn mice may affect cognition by disturbing the emotional and behavioral components of the learning process.

Adrenocorticotropic Hormone↗

PubMed2005

Retinal degeneration 12 (rd12): a new, spontaneously arising mouse model for human Leber congenital amaurosis (LCA).

PURPOSE: To report the phenotype and characterization of a new, naturally occurring mouse model of hereditary retinal degeneration (rd12). METHODS: The retinal phenotype of rd12 mice were studied using serial indirect ophthalmoscopy, fundus photography, electroretinography (ERG), genetic analysis including linkage studies and gene identification, immunohistochemistry, and biochemical analysis. RESULTS: Mice homozygous for the rd12 mutation showed small punctate white spots on fundus examination at 5 months of age. The retina in the rd12 homozygote had a normal appearance at the light microscopic level until 6 weeks of age when occasional voids appeared in the outer segments (OS) of the photoreceptor (PR) cells. The outer nuclear layer (ONL) appeared normal until 3 months of age though more obvious voids were detected in the OS. By 7 months of age, 6 to 8 layers of ONL remained in the mutant retina, and the OS were obviously shorter. The first sign of retinal degeneration was detected at the electron microscopic level around 3 weeks of age when occasional small lipid-like droplets were detected in the retinal pigment epithelium (RPE). By 3 months of age, much larger, lipid-like droplets accumulated in RPE cells accompanied by some OS degeneration. While the histology indicated a relatively slow retinal degeneration in the rd12 homozygous mutant mice, the rod ERG response was profoundly diminished even at 3 weeks of age. Genetic analysis showed that rd12 was an autosomal recessive mutation and mapped to mouse chromosome 3 closely linked to D3Mit19, a location known to be near the mouse Rpe65 gene. Sequence analysis showed that the mouse retinal degeneration is caused by a nonsense mutation in exon 3 of the Rpe65 gene, and the gene symbol for the rd12 mutation has been updated to Rpe65rd12 to reflect this. No RPE65 expression, 11-cis retinal, or rhodopsin could be detected in retinas from rd12 homozygotes, while retinyl esters were found to accumulate in the retinal pigment epithelium (RPE). CONCLUSIONS: Mutations in the retinal pigment epithelium gene encoding RPE65 cause an early onset autosomal recessive form of human retinitis pigmentosa, known as Leber congenital amaurosis (LCA), which results in blindness or severely impaired vision in children. A naturally arising mouse Rpe65 mutation provides a good model for studying the pathology of human RPE65 mutations and the effects of retinyl ester accumulation.

Animals↗

PubMed2005

Discovery genetics: serendipity in basic research.

The role of serendipity in science has no better example than the discovery of spontaneous mutations that leads to new mouse models for research. The approach of finding phenotypes and then carrying out genetic analysis is called forward genetics. Serendipity is a key component of discovering and developing mice with spontaneous mutations into animal models of human disease. In this article, the role of serendipity in discovering and developing mouse models is described within a program at The Jackson Laboratory that capitalizes on serendipitous discoveries in large breeding colonies. Also described is how any scientists working with mice can take advantage of serendipitous discoveries as a research strategy to develop new models. Spontaneous mutations cannot be planned but happen in all research mouse colonies and are discovered as unexpected phenotypes. The alert scientist or technician can rationally exploit such chance observations to create new research opportunities.

Animals↗

PubMed2004

New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice.

X-linked hypophosphatemic rickets (XLH) in humans is caused by mutation in the PHEX gene. Previously, three mutations in the mouse Phex gene have been reported: Phex(Hyp), Gy, and Phex(Ska1). Here we report analysis of two new spontaneous mutation in the mouse Phex gene, Phex(Hyp-2J) and Phex(Hyp-Duk). Phex(Hyp-2J) and Phex(Hyp-Duk) involve intragenic deletions of at least 7.3 kb containing exon 15, and 30 kb containing exons 13 and 14, respectively. Both mutations cause similar phenotypes in males, including shortened hind legs and tail, a shortened square trunk, hypophosphatemia, hypocalcemia, and rachitic bone disease. In addition, mice carrying the Phex(Hyp-Duk) mutation exhibit background-dependent variable expression of deafness, circling behavior, and cranial dysmorphology, demonstrating the influence of modifying genes on Phex-related phenotypes. Cochlear cross-sections from Phex(Hyp-2J)/Y and Phex(Hyp-Duk)/Y males reveal a thickening of the temporal bones surrounding the cochlea with the presence of a precipitate in the scala tympani. Evidence of the degeneration of the organ of Corti and spiral ganglion also are present in the hearing-impaired Phex(Hyp-Duk)/Y mice, but not in the normal-hearing Phex(Hyp-2J)/Y mice. Analysis of the phenotypes noted in Phex(Hyp-Duk)/Y and Phex(Hyp-2J)/Y males, together with those noted in Phex(Ska1)/Y and Phex(Hyp)/Y males, now allow XLH-related phenotypes to be separated from non-XLH-related phenotypes, such as those noted in Gy/Y males. Also, identification of the genetic modifiers of hearing and craniofacial dysmorphology in Phex(Hyp-Duk)/Y mice could provide insight into the phenotypic variation of XLH in humans.

Absorptiometry, Photon↗

PubMed2004

Operant conditioning in the Ts65Dn mouse: learning.

Ts65Dn and littermate controls were trained to respond (nose-poke) under operant schedules of reinforcement. A small difference was observed in the initial operant training of the Ts65Dn mouse that disappeared with training under a fixed-ratio 15 schedule of milk presentation. No difference was observed in a position reversal task in which mice initially trained to respond upon one photocell had to learn to respond on a previously inactive photocell. Under an incremental repeated acquisition of behavioral chains schedule, no difference was observed when one or two responses were required to complete the sequence. However, when three or four responses were required to complete the sequence, a marked deficit was observed in the Ts65Dn mice. These results show that both Ts65Dn and littermate controls can be trained to respond under operant schedules of reinforcement, but that Ts65Dn mice have a learning deficit that is correlated with task difficulty.

Animals↗

PubMed2004

Building protein interaction maps for Down's syndrome.

Now that the complete sequences for human chromosome 21 and the orthologous mouse genomic regions are known, reasonably complete, conserved, protein-coding gene catalogues are also available. The central issue now facing Down's syndrome researchers is the correlation of increased expression of specific, normal, chromosome 21 genes with the development of specific deficits in learning and memory. Because of the number of candidate genes involved, the number of alternative splice variants of individual genes and the number of pathways in which these genes function, a pathway analysis approach will be critical to success. Here, three examples, both gene specific and pathway related, that would benefit from pathway analysis are discussed: (1) the potential roles of eight chromosome 21 proteins in RNA processing pathways; (2) the chromosome 21 protein intersectin 1 and its domain composition, alternative splicing, protein interactions and functions; and (3) the interactions of ten chromosome 21 proteins with components of the mitogen-activated protein kinase and the calcineurin signalling pathways. A productive approach to developing gene-phenotype correlations in Down's syndrome will make use of known and predicted functions and interactions of chromosome 21 genes to predict pathways that may be perturbed by their increased levels of expression. Investigations may then be targeted in animal models to specific interactions, intermediate steps or end-points of such pathways and the downstream - perhaps amplified - consequences of gene dosage directly assessed. Once pathway perturbations have been identified, the potential for rational design of therapeutics becomes practical.

Animals↗

PubMed2003

Mouse models of Down syndrome: how useful can they be? Comparison of the gene content of human chromosome 21 with orthologous mouse genomic regions.

With an incidence of approximately 1 in 700 live births, Down syndrome (DS) remains the most common genetic cause of mental retardation. The phenotype is assumed to be due to overexpression of some number of the >300 genes encoded by human chromosome 21. Mouse models, in particular the chromosome 16 segmental trisomies, Ts65Dn and Ts1Cje, are indispensable for DS-related studies of gene-phenotype correlations. Here we compare the updated gene content of the finished sequence of human chromosome 21 (364 genes and putative genes) with the gene content of the homologous mouse genomic regions (291 genes and putative genes) obtained from annotation of the public sector C57Bl/6 draft sequence. Annotated genes fall into one of three classes. First, there are 170 highly conserved, human/mouse orthologues. Second, there are 83 minimally conserved, possible orthologues. Included among the conserved and minimally conserved genes are 31 antisense transcripts. Third, there are species-specific genes: 111 spliced human transcripts show no orthologues in the syntenic mouse regions although 13 have homologous sequences elsewhere in the mouse genomic sequence, and 38 spliced mouse transcripts show no identifiable human orthologues. While these species-specific genes are largely based solely on spliced EST data, a majority can be verified in RNA expression experiments. In addition, preliminary data suggest that many human-specific transcripts may represent a novel class of primate-specific genes. Lastly, updated functional annotation of orthologous genes indicates genes encoding components of several cellular pathways are dispersed throughout the orthologous mouse chromosomal regions and are not completely represented in the Down syndrome segmental mouse models. Together, these data point out the potential for existing mouse models to produce extraneous phenotypes and to fail to produce DS-relevant phenotypes.

Alternative Splicing↗

PubMed2003

Curly bare (cub), a new mouse mutation on chromosome 11 causing skin and hair abnormalities, and a modifier gene (mcub) on chromosome 5.

In the outcrossing of a new recessive mouse mutation causing hair loss, a new wavy-coated phenotype appeared. The two distinct phenotypes were shown to be alternative manifestations of the same gene mutation and attributable to a single modifier locus. The new mutation, curly bare (cub), was mapped to distal Chr 11 and the modifier (mcub) was mapped to Chr 5. When homozygous for the recessive mcub allele, cub/cub mice appear hairless. A single copy of the dominant Mcub allele confers a full, curly coat in cub/cub mice. Reciprocal transfer of full-thickness skin grafts between mutant and control animals showed that the skin phenotype was tissue autonomous. The hairless cub/cub mcub/mcub mice show normal contact sensitivity responses to oxazolone. The similarity of the wavy coat phenotype to those of Tgfa and Egfr mutations and the map positions of cub and mcub suggest candidate genes that interact in the EGF receptor signal transduction pathway.

Animals↗

PubMed2003

A missense mutation in the mouse Col2a1 gene causes spondyloepiphyseal dysplasia congenita, hearing loss, and retinoschisis.

UNLABELLED: A missense mutation in the mouse Col2a1 gene has been discovered, resulting in a mouse phenotype with similarities to human spondyloepiphyseal dysplasia (SED) congenita. In addition, SED patients have been identified with a similar molecular mutation in human COL2A1. This mouse model offers a useful tool for molecular and biological studies of bone development and pathology. INTRODUCTION: A new mouse autosomal recessive mutation has been discovered and named spondyloepiphyseal dysplasia congenita (gene symbol sedc). MATERIALS AND METHODS: Homozygous sedc mice can be identified at birth by their small size and shortened trunk. Adults have shortened noses, dysplastic vertebrae, femora, and tibias, plus retinoschisis and hearing loss. The mutation was mapped to Chr15, and Col2a1 was identified as a candidate gene. RESULTS: Sequence analyses revealed that the affected gene is Col2a1, which has a missense mutation at exon 48 causing an amino acid change of arginine to cysteine at position 1417. Two human patients with spondyloepiphyseal dysplasia (SED) congenita have been reported with the same amino acid substitution at position 789 in the human COL2A1 gene. CONCLUSIONS: Thus, sedc/sedc mice provide a valuable model of human SED congenita with molecular and phenotypic homology. Further biochemical analyses, molecular modeling, and cell culture studies using sedc/sedc mice could provide insight into mechanisms of skeletal development dependent on Col2a1 and its role in fibril formation and cartilage template organization.

Amino Acid Sequence↗

PubMed2003

In collaboration: the Jackson Laboratory Craniofacial Resource.

Dr. Sandy C. Marks, Jr., has been a longtime collaborator of the Mouse Mutant Resource at The Jackson Laboratory and, most recently, was involved in the development of a Craniofacial Resource at TJL. The goals of this resource are to discover and supply to the scientific community mouse models of human craniofacial disease. A brief description of this collaboration is presented in Sandy's honor.

Animals↗

PubMed2003

Quantitative PCR genotyping assay for the Ts65Dn mouse model of Down syndrome.

The Ts65Dn mouse is a segmentally trisomic model for Down syndrome. Until now, Ts65Dn mice have been identified by the laborious methods of either chromosomal analysis of cultured peripheral lymphocytes or fluorescent in situ hybridization (FISH). We report here a quantitative PCR method for genotyping Ts65Dn mice, as well as a phenotypic description for visually preclassifying mice to be genotyped.

Algorithms↗

PubMed2002

Differential effects of environmental enrichment on behavior and learning of male and female Ts65Dn mice, a model for Down syndrome.

We have assessed the effects of enriched environment (EE) upon behavioral and cognitive performances of partially trisomic Ts65Dn (TS) mice and their control (CO) littermates. Enriched environment was applied to pups for 7 weeks after weaning. Circadian spontaneous activity (actimetry), exploratory behavior (hole board), activity in the open field and spatial memory (Morris Water Maze, repeated acquisition and cued paradigms) were analyzed in 86 female and 75 male mice, starting 15 days after completing enrichment. For each gender, mice were distributed in non-enriched and enriched control and trisomic groups. Enriched environment reduced in trisomic females and enhanced in trisomic males' circadian activity. Exploratory behavior was increased by enrichment in all groups, regardless of gender or presence of trisomy. In the Morris Water Maze, a significant improvement of the spatial memory was observed in enriched-control females, but not in enriched-control male mice, as assessed by distances traveled. Performances in the four groups of control animals were also consistently and significantly better than those of matching trisomic mice. In the acquisition trials, enrichment improved performance in trisomic female animals, but deteriorated in trisomic male mice. In all groups, changes in escape latencies and distances induced by enrichment were accounted for by changes in the total time spent in the periphery of the pool, indicating changes in learning strategy. Working memory was the function more affected by enrichment. It is concluded that enriched environment induces behavioral and learning changes in trisomic mice, although gender plays a significant modulatory role.

Animals↗