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M T Davisson

Publications and source records attributed to M T Davisson.

At least 73 records · Page 4Linked to original sources
PubMed1995

A mouse model for Down syndrome exhibits learning and behaviour deficits.

Trisomy 21 or Down syndrome (DS) is the most frequent genetic cause of mental retardation, affecting one in 800 live born human beings. Mice with segmental trisomy 16 (Ts65Dn mice) are at dosage imbalance for genes corresponding to those on human chromosome 21q21-22.3--which includes the so-called DS 'critical region'. They do not show early-onset of Alzheimer disease pathology; however, Ts65Dn mice do demonstrate impaired performance in a complex learning task requiring the integration of visual and spatial information. The reproducibility of this phenotype among Ts65Dn mice indicates that dosage imbalance for a gene or genes in this region contributes to this impairment. The corresponding dosage imbalance for the human homologues of these genes may contribute to cognitive deficits in DS.

Alzheimer Disease↗
PubMed1994

Rules and guidelines for nomenclature of mouse genes. International Committee on Standardized Genetic Nomenclature for Mice.

Guidelines for mouse genetic nomenclature were developed in the 1940s and have been revised several times since. The most recent revision was completed by the International Committee on Standardized Genetic Nomenclature in Mice. The basic rules for naming and symbolizing mouse mutant genes and polymorphic loci are summarized here with reference to sources of the complete rules for genes, strains and chromosomal anomalies.

Animals↗
PubMed1994

Differential expression of a new dominant agouti allele (Aiapy) is correlated with methylation state and is influenced by parental lineage.

The agouti gene normally confers the wild-type coat color of mice. Dominant mutations at the agouti locus result in a pleiotropic syndrome that is characterized by excessive amounts of yellow pigment in the coat, obesity, a non-insulin-dependent diabetic-like condition, and the propensity to form a variety of tumors. Here, we describe a new dominant mutation at the agouti locus in which an intracisternal A-particle (IAP) has integrated in an antisense orientation immediately 5' of the first coding exon of the gene. This mutation, which we have named Aiapy, results in the ectopic expression of the agouti gene through the utilization of a cryptic promoter within the IAP 5' long terminal repeat (LTR). The coat color of Aiapy/-mice ranges from solid yellow to a pigment pattern that is similar to wild type (pseudoagouti), and the expressivity of this mutant phenotype varies with parental inheritance. Those offspring with a yellow coat ectopically express agouti mRNA at high levels and exhibit marked obesity, whereas pseudoagouti mice express agouti mRNA at a very low level and their weights do not differ from wild-type littermates. Data are presented to show that the differential expressivity of the Aiapy allele is correlated with the methylation status of the inserted IAP 5' LTR. These data further support the hypothesis that in dominant yellow mutations at the agouti locus, it is the ubiquitous expression of the wild-type agouti coding sequence that is responsible for the yellow coat color, obesity, diabetes, and tumorigenesis.

Agouti Signaling Protein↗
PubMed1994

The mouse congenital polycystic kidney (cpk) locus maps within 1.3 cM of the chromosome 12 marker D12Nyu2.

The mouse congenital polycystic kidney (cpk) mutation causes bilateral cystic dilatation of the renal collecting tubules and leads to rapidly progressive renal insufficiency in affected homozygotes. The phenotype of the cpk/cpk mutants closely resembles that of human autosomal recessive polycystic kidney disease (ARPKD). Previously, we have reported that the cpk locus maps close to D12Nyu2 on Chromosome (Chr) 12. To determine the cpk map location more precisely, we have extended our previous studies using additional progeny and additional markers of proximal Chr 12. These recent studies position cpk within 1.3 cM of D12Nyu2, closely flanked by (Odc, D12Mit10) and (Tpo, D12Mit12). Our data support an ordered array of seven DNA markers that will provide reference points for building a physical map of the Chr 12 region centered on cpk. Moreover, these data establish that cpk lies within a linkage group that is conserved between mouse Chr 12 and human chr 2p24-2p25. This assignment to a region of homology will facilitate human linkage analyses to determine whether mouse cpk and human ARPKD are mutations of homologous genes.

Animals↗
PubMed1994

Molecular analysis of reverse mutations from nonagouti (a) to black-and-tan (a(t)) and white-bellied agouti (Aw) reveals alternative forms of agouti transcripts.

The agouti gene regulates the differential production of eumelanin (black or brown) and phaeomelanin (yellow) pigment granules by melanocytes in the hair follicles of mice. The original nonagouti (a) allele, which confers a predominantly black coat color, has been shown to revert to two other more dominant agouti alleles, black-and-tan (a(t)) and white-bellied agouti (Aw), with an exceptionally high frequency. The a(t) and Aw alleles confer phenotypes in which the pigmentation is not uniformly distributed over the dorsal and ventral surfaces of the animal; in both cases the ventral surface of the animal is markedly lighter than the dorsal surface due to an increase in phaeomelanin production. To understand the unusually high reversion rate of a to a(t) or Aw, and to decipher the molecular events associated with the different pigmentation patterns associated with these three agouti alleles, we have characterized a, a(t) and Aw at the molecular level. Here, we report that insertions of 11, 6, and 0.6 kb are present at precisely the same position in the first intron of the agouti gene in a, a(t), and Aw, respectively. The a insertion consists of a 5.5-kb VL30 element that has incorporated 5.5 kb of additional sequence internally; this internal sequence is flanked by 526-bp direct repeats. The a(t) allele contains only the VL30 element and a single, internal 526-bp repeat. The Aw allele has only a solo VL30 LTR. Based on the comparison of the structure of the a(t) and Aw insertions, we propose that reverse mutations occur by excision of inserted sequences in a through homologous recombination, utilizing either the 526-bp direct repeats to generate a(t) or the VL30 LTRs to generate Aw. Moreover, the analysis of these three alleles has allowed us to identify additional exons of the agouti gene that give rise to alternatively processed forms of agouti mRNA. We demonstrate that the distinct insertions in a, a(t) and Aw cause pigmentation differences by selectively inactivating the expression of different forms of agouti transcripts.

Alleles↗
PubMed1994

The stumbler mutation maps to proximal mouse chromosome 2.

The cerebellar mouse mutation stumbler (stu) was mapped to proximal Chromosome (Chr) 2 with a recently developed polymerase chain reaction assay for endogenous retroviruses that vary between mouse strains. The stu locus resides between the markers D2Mit5 and D2Mit7. A number of developmentally or neurologically relevant candidate genes map in this region, including Bmi1, Dbh, Grin1, Notch1, Pax8, Rxra, and Spna2. Knowing the chromosomal localization of stu should simplify maintenance of the stumbler mouse stock and also enable analysis of the cerebellar defect in presymptomatic individuals.

Animals↗
PubMed1994

Identification and genetic mapping of 151 dispersed members of 16 ribosomal protein multigene families in the mouse.

More than 150 individual members of 16 ribosomal protein multigene families were identified as DNA restriction fragments and genetically mapped. The ribosomal protein gene-related sequences are widely dispersed throughout the mouse genome. Map positions were determined by analysis of 144 progeny mice from both an interspecific (C57BL/6J x SPRET/Ei)F1 x SPRET/Ei and an intersubspecific (C57BL/6J x CAST/Ei)F1 x C57BL/6J backcross. In addition, 30 members of the multigene families encoding PGK1 ODC, and TPI, including five new loci for ODC and one new locus for TPI, were characterized and mapped. Interspecific backcross linkage data for 29 nonecotropic murine leukemia retroviruses endogenous to C57BL/6J mice are also reported. Transmission ratio distortions and recombination frequencies are compared between the two backcrosses.

Animals↗
PubMed1994

A frameshift mutation in the mouse alpha 1 glycine receptor gene (Glra1) results in progressive neurological symptoms and juvenile death.

The neurologic mutant mouse, oscillator, is characterized by a fine motor tremor and muscle spasms that begin at 2 weeks of age and progressively worsen, resulting in death by 3 weeks of age. We report the localization of the oscillator mutation to the central region of mouse Chr 11, and demonstrate its allelism with spasmodic, a recessive viable neurological mutation which displays excessive startle. Oscillator is caused by a microdeletion in the gene coding for the alpha 1 subunit of the adult glycine receptor (Glra1). Glra1 assembles into a pentameric complex with the beta subunit of the glycine receptor (3 alpha (1)2 beta 5) to form a glycine-gated chloride channel. This receptor is the major adult glycine receptor, and the site of action of the poison strychnine. The oscillator deletion causes a frameshift resulting in loss of the highly conserved third cytoplasmic loop and fourth transmembrane domain of the protein. Membranes isolated from oscillator homozygote spinal cords display a 90% reduction in glycine-displaceable strychnine binding. This lack of ligand binding function confirms that oscillator is a complete loss of function allele. The oscillator mutation provides evidence that although at least four different alpha subunits exist for the glycine receptor, none of the other subunits can compensate for the loss of alpha 1 function. Mutations which impair GLRA1 function in humans have been shown to cause dominant familial startle disease. The identification of the oscillator mutation suggests that severe loss of function alleles in humans would result in prenatal or neonatal lethality.

Amino Acid Sequence↗
PubMed1994

Adrenocortical dysplasia: a mouse model system for adrenocortical insufficiency.

A spontaneous autosomal recessive mutation causing disordered morphogenesis of the adrenal cortex has been identified in DW/J inbred strain mice and named adrenocortical dysplasia (acd). The acd mutant gene has been mapped just proximal to oligosyndactyly (Os) and esterase-1 (Es-1) in the central region of chromosome 8. Both male and female acd/acd mice are characterized by reduced survival, retarded growth, skin hyperpigmentation, poorly developed pelage and focal ureteral blockage leading to hydronephrosis. Morphometric measurements showed that acd/acd cortical cells and nuclei were increased sevenfold in volume; nuclei often showed a variety of inclusions. Cortical cells of acd/acd mice contained large numbers of mitochondria, smooth endoplasmic reticulum and lipid droplets characteristic of steroidogenic cells. While cortical X-zones failed to develop in acd/acd adrenals, medullary cells and nuclei were unaffected by mutant gene action. Resting serum corticosterone levels in female, but not male, mutant mice were significantly lower than in +/? normal littermates, whereas ACTH levels were significantly elevated in mutants of both sexes. Serum aldosterone levels were normal in acd/acd mice. Functional studies of adrenals cultured in vitro revealed that acd/acd adrenals secreted reduced amounts of corticosterone per pair of glands under both basal and ACTH-stimulated conditions. However, correction of the corticosterone secretion data to mg cortical mass in culture showed that the mutant cortical tissue secreted the same amount of glucocorticoid as did their +/? normal littermate glands. We conclude that the acd mutant gene acts in an unknown fashion to cause a fundamental defect in cellular proliferation in the adrenal cortex, leading to compensatory marked hypertrophy of cortical cells and grossly enlarged nuclei. The role of acd action in adrenal cortical development remains to be established.

Adrenal Cortex↗
PubMed1993

Defective pro alpha 2(I) collagen synthesis in a recessive mutation in mice: a model of human osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a heritable disorder of connective tissue associated with fractures, osteopenia, and short stature. OI results from mutations affecting the pro alpha 1 or pro alpha 2 gene of type I collagen. We describe a strain of mice with a nonlethal recessively inherited mutation (oim) that results in phenotypic and biochemical features that simulate moderate to severe human OI. The phenotype of homozygous oim mice includes skeletal fractures, limb deformities, generalized osteopenia, and small body size. Their femurs are smaller and demonstrate marked cortical thinning and fewer medullary trabeculae than those of wild-type mice. Breeding studies show the mutation is inherited in most crosses as a single recessive gene on chromosome 6, near the murine Cola-2 gene. Biochemical analysis of skin and bone, as well as isolated dermal fibroblast cultures, demonstrate that alpha 1(I) homotrimeric collagen accumulates in these tissues and is secreted by fibroblasts. Short labeling studies in fibroblasts demonstrate an absence of pro alpha 2(I) collagen chains. Nucleotide sequencing of the cDNA encoding the COOH-propeptide reveals a G deletion at pro alpha 2(I) nucleotide 3983; this results in an alteration of the sequence of the last 48 amino acids. The oim mouse will facilitate the study of type I collagen-related skeletal disease.

Amino Acid Sequence↗
PubMed1993

Motor neuron degeneration of mice is a model of neuronal ceroid lipofuscinosis (Batten's disease).

Pathological studies of mice homozygous for the motor neuron degeneration (Mnd) mutation show abnormalities similar to those of the human neuronal ceroid lipofuscinoses: sudanophilic, autofluorescent intraneuronal inclusions that are immunoreactive with antibodies to subunit c of mitochondrial ATP synthase. Ultrastructurally, the inclusions have the pentalaminar structure characteristic of some form of human neuronal ceroid lipofuscinosis and of canine and ovine models of neuronal ceroid lipofuscinosis. Similar inclusions are observed in many somatic organs and in the retina, which develops photoreceptor degeneration. This mutation, previously considered a model of amyotrophic lateral sclerosis, may be a useful model for molecular and genetic studies of human neuronal ceroid lipofuscinosis because mice have been well characterized genetically. Since they are inexpensive to breed and maintain, they can also be used to test therapeutic interventions.

Animals↗
PubMed1993

Identification and genetic mapping of the murine gene and 20 related sequences encoding chromosomal protein HMG-17.

HMG-17 is an abundant, nonhistone chromosomal protein that binds preferentially to nucleosomal core particles of mammalian chromatin. The human gene for HMG-17 has been localized to Chromosome (Chr) 1p, but the murine gene has not been previously mapped. Here we identify the murine functional gene, Hmg17, from among more than 25 related sequences (probably processed pseudogenes) and show that it is located on mouse Chr 4, in a region known to have conserved linkage relationships with human Chr 1p. We also report the map locations of 20 additional Hmg17-related sequences on mouse Chrs 1, 2, 3, 5, 7, 8, 9, 13, 15, 16, 17, 18, and X. The multiple, dispersed members of the Hmg17 multigene family can be detected efficiently with a single cDNA probe and provide useful markers for genetic mapping studies in mice.

Animals↗
PubMed1993

Recombination suppression by heterozygous Robertsonian chromosomes in the mouse.

Robertsonian chromosomes are metacentric chromosomes formed by the joining of two telocentric chromosomes at their centromere ends. Many Robertsonian chromosomes of the mouse suppress genetic recombination near the centromere when heterozygous. We have analyzed genetic recombination and meiotic pairing in mice heterozygous for Robertsonian chromosomes and genetic markers to determine (1) the reason for this recombination suppression and (2) whether there are any consistent rules to predict which Robertsonian chromosomes will suppress recombination. Meiotic pairing was analyzed using synaptonemal complex preparations. Our data provide evidence that the underlying mechanism of recombination suppression is mechanical interference in meiotic pairing between Robertsonian chromosomes and their telocentric partners. The fact that recombination suppression is specific to individual Robertsonian chromosomes suggests that the pairing delay is caused by minor structural differences between the Robertsonian chromosomes and their telocentric homologs and that these differences arise during Robertsonian formation. Further understanding of this pairing delay is important for mouse mapping studies. In 10 mouse chromosomes (3, 4, 5, 6, 8, 9, 10, 11, 15 and 19) the distances from the centromeres to first markers may still be underestimated because they have been determined using only Robertsonian chromosomes. Our control linkage studies using C-band (heterochromatin) markers for the centromeric region provide improved estimates for the centromere-to-first-locus distance in mouse chromosomes 1, 2 and 16.

Animals↗