Motheaten, an immunodeficient mutant of the mouse. II. Depressed immune competence and elevated serum immunoglobulins.

Mice homozygous for the recessive mutation motheaten (me) are deficient in capacity for immune response but show an elevated level of serum immunoglobulins. In comparison to spleen cells from normal sibs, spleen cells from me/me mice have a severely depressed 19S PFC response to SRBC. In the GVH assay, spleen and thymus cells from motheaten donors caused significantly weaker reactions than like cells from normal sibs. Serum electrophoretic patterns of motheaten mice showed increased levels of alpha-, beta-, and gamma-globulins and decreased levels of albumin. Increases in quantities of all major classes of immunoglobulins were found in serum of me/me mice 5 weeks of age and older. Elevation of serum IgM was evident by 3 weeks of age and had reached 25 times the levels in normal sibs by 6 weeks of age. Immunoelectrophoresis and Ouchterlony analysis showed motheaten serum to have both kappa and lambda2 light chains. Evidence of autoimmunity was found in motheaten mice in the granular deposition of IgM and IgG in kidney glomeruli. Motheaten mice, thus, appear to have a severe immune deficiency, but the basic nature of the deficiency is not yet known.     

Hereditary chondrodystrophy in the rabbit. Genetics and pathology of a new mutant, a model for metatropic dwarfism.

Thirty-one cases of a new hereditary chondrodystrophy in the rabbit have been shown to be associated with a fully penetrant autosomal recessive gene symbolized cd. The mutant is viable prenatally but does not survive after birth. It differs from the two other inherited chondrodystrophies, dachs and achondroplasia, but is very similar to the metatropic dwarf reported in man.     

Evaluation of the mouse mutant wasted as an animal model for ataxia telangiectasia. I. Age-dependent and tissue-specific effects

The wasted mouse, an animal model proposed for the genetically transmitted human disease ataxia telangiectasia (AT), was examined for its biological, cytogenetic and biochemical properties. In affected homozygotes, a marked age-dependent decrease in the ratio of spleen and thymus to body weight, and a slight but significant decrease in the liver to body weight ratio were observed while no such change was found in the kidney. An age-dependent increase was observed in the frequency of both spontaneous and gamma-ray-induced chromosomal aberrations in bone marrow cells of wasted mice. In littermate control mice, neither of these alterations was observed in an age-dependent manner. The activity of a primer activating enzyme, which has been reported to be deficient in AT cells, also decreased with age in spleen cells, but not in liver cells of affected mice. However, alterations in apurinic DNA endonuclease activity were not detected in the developmental stages examined. These data indicate that this mouse mutant may serve as a useful animal model for studying the relationships between DNA repair and lymphoid tissue differentiation.     

Genetics and characterization of an open flower mutant in chickpea

The chickpea (Cicer arietinum L.) is a self-pollinated grain legume with cleistogamous flowers. A spontaneous open-flower mutant, designated OFM-3, was identified in which reproductive organs were not enclosed by the keel petals and thus remained exposed. All 10 stamens in this mutant were free, whereas these are in diadelphous (9 fused + 1 free) condition in normal chickpea flowers. A large number of pods (73%) remained unfilled (empty) in OFM-3, though its pollen fertility was as high as the standard cultivars. The open-flower trait was found to be recessive and controlled by a single gene. OFM-3 was crossed with earlier reported open-flower mutants, ICC 16341 and ICC 16129, to establish trait relationships of genes controlling open flower traits in these mutants. It was found that each of these mutants has a unique gene for open flower trait. The genes controlling open flower trait in ICC 16341, ICC 16129, and OFM-3 were designated ofl-1, ofl-2, and ofl-3, respectively. Breeding lines with open flower trait and higher percentage of filled pods have been developed from the progenies of the crosses of OFM-3 with normal-flowered lines. The open flower trait offers opportunity for exploring hybrid technology in the chickpea.     

Nuclear suppressors of the [poky] cytoplasmic mutant in Neurospora crassa. I. Genetics and respiratory properties.

Six nuclear suppressors of the (poky) cytoplasmic mutant (sup-1, sup-3, sup-4, sup-5, sup-10, sup-14) have been obtained in Neurospora crassa. The sup genes suppress the slow growth phenotype of (poky), and alleviate, at least partially, the deficiency of cyanide sensitive respiratory activity in the mycelium of this cytoplasmic mutant. The six suppressors are nonallelic, suppress the phenotypic effects of (stp-Bl) in addition to (poky), but have no effect on the phenotype expression of the (mi-3) cytoplasmic mutant. On the basis of experimentally established molecular defects in (poky) and on the basis of hypothetical consideration, it is proposed that the sup mutations affect the structure and properties of mitochondrial ribosomal proteins.     

Motheater: an immunodeficient mouse with markedly less ability to survive that the nude mouse in a germfree environment.

The motheaten mouse is an immunodeficient mutant which has been found to have elevated immunoglobulin levels, to exhibit autoimmunity, and early death. Since survival is not improved by a germfree environment, it appears that some mechanism other than infection results in its early demise.     

Molecular analysis of an acatalasemic mouse mutant

The Csb acatalasemia mouse mutant differentially expresses reduced levels of catalase activity in a tissue specific manner. In order to pinpoint the molecular lesion that imparts the acatalasemia phenotype in Csb mice we have utilized the polymerase chain reaction technique to isolate catalase cDNA clones from control and Csb mouse strains. Sequence analyses of these cDNA clones have revealed a single nucleotide difference within the coding region of catalase between control and Csb mice. This nucleotide transversion (G----T) is located in the third position of amino acid 11 in the catalase monomer. In control mouse strains glutamine (CAG) is encoded at amino acid 11, while in Csb mice this codon (CAT) encodes histidine. This amino acid is located within a region that forms the first major alpha-helix in the amino-terminal arm of the catalase subunit and, as such, may render the catalase molecule unstable under certain physiological conditions.     

Statistical Genetics of an Annual Plant, Impatiens Capensis. I. Genetic Basis of Quantitative Variation

Analysis of quantitative genetics in natural populations has been hindered by computational and methodological problems in statistical analysis. We developed and validated a jackknife procedure to test for existence of broad sense heritabilities and dominance or maternal effects influencing quantitative characters in Impatiens capensis. Early life cycle characters showed evidence of dominance and/or maternal effects, while later characters exhibited predominantly environmental variation. Monte Carlo simulations demonstrate that these jackknife tests of variance components are extremely robust to heterogeneous error variances. Statistical methods from human genetics provide evidence for either a major locus influencing germination date, or genes that affect phenotypic variability per se. We urge explicit consideration of statistical behavior of estimation and testing procedures for proper biological interpretation of statistical results.     

Genetics and bone. Using the mouse to understand man

The rationale for use of inbred strains of mice in bone research is well recognized and includes: a) practical factors (economics of scale, rapid development of adult status, pre-existing knowledge, down-sized technologies) and b) proven methodologies for genetic studies (polygenic trait analyses, mapping tools, genomic sequencing, methods for gene manipulation). Initial investigations of inbred strains of mice showed that femoral and lumbar vertebral volumetric bone mineral density (BMD, mg/mm(3)) by pQCT varied in excess of 50% for femurs and 9% in vertebral BMD. Two strains - low BMD C57BL/6J (B6) mice and high BMD C3H/HeJ (C3H) - were investigated for insights to their BMD diversity. B6C3F2 females derived from intercrossing B6C3F1s were raised to adult skeletal status at 4 months, then necropsied for phenotyping of bone and genotyping of genomic DNA. 1000 F2 females were genotyped for PCR product polymorphisms on all 19 autosomes at approximately 15 cM. Genome wide analyses for genotype-phenotype correlations showed 10 chromosomes (Chrs) carried genes for femoral and 7 Chrs for vertebral BMD. LOD scores ranged from 2.90 to 24.4, and percent of F2 variance accounted for ranged from 1 to 10%. Analyses of main effects revealed both dominant-recessive and additive inheritance patterns. Both progenitor strains carried alleles with positive and negative effects on BMD of each bone sites. A remarkable array of additonal skeletal phenotypes (femur and vertebral geometry, strength measures, serum markers) also proved polygenic in nature, with complex segregation patterns. Verification of BMD quantitative trait loci (QTLs) was undertaken by creating congenic B6 strains carrying individual QTL regions from C3H. Following 6 cycles of backcrossing a QTL-containing region from C3H to the B6 strain, N6F2 congenic strain mice were aged to 4 months, then genotyped for the QTL region and phenotyped for skeletal traits. Comparison of mice homozygous for C3H alleles versus homozygous for B6 alleles in the QTL regions showed that femoral BMD increased or decreased significantly in congenic strains, as was predicted from F2 data. Gender differences specific to BMD QTLs have been revealed, as have more than 30 additional phenotypes associated with cortical and trabecular structural parameters and biomechanical properties.     

Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model

Non-alcoholic steatohepatitis (NASH) is a frequent clinical picture characterised by hepatic inflammation, lipid accumulation and fibrosis. When untreated, NASH bears a high risk of developing liver cirrhosis and consecutive hepatocellular carcinoma requiring liver transplantation in its end-stage. However, donor organ scarcity has prompted the search for alternatives, of which hepatocyte or stem cell-derived hepatocyte transplantation are regarded auspicious options of treatment. Mesenchymal stem cells (MSC) are able to differentiate into hepatocyte-like cells and thus may represent an alternative cell source to primary hepatocytes. In addition these cells feature anti-inflammatory and pro-regenerative characteristics, which might favour liver recovery from NASH. The aim of this study was to investigate the potential benefit of hepatocyte-like cells derived from human bone marrow MSC in a mouse model of diet-induced NASH. Seven days post-transplant, human hepatocyte-like cells were found in the mouse liver parenchyma. Triglyceride depositions were lowered in the liver but restored to normal in the blood. Hepatic inflammation was attenuated as verified by decreased expression of the acute phase protein serum amyloid A, inflammation-associated markers (e.g. lipocalin 2), as well as the pro-inflammatory cytokine TNFα. Moreover, the proliferation of host hepatocytes that indicate the regenerative capacity in livers receiving cell transplants was enhanced. Transplantation of MSC-derived human hepatocyte-like cells corrects NASH in mice by restoring triglyceride depositions, reducing inflammation and augmenting the regenerative capacity of the liver.     

Circling mouse, a spontaneous mutant in the inner ear.

A spontaneous mutant was established in the ICR mouse strain. The affected mice became hyperactive at about 7 days of age, and then showed circling behavior. The body weight decreased significantly 2 weeks after birth, and developmental defects were revealed in the middle ear, cochlea, cochlear nerve, and semicircular canal areas. The mutation was inherited by an autosomal single recessive gene and is referred to as cir.     

Infant vocalization, adult aggression, and fear behavior of an oxytocin null mutant mouse

Previous studies have shown that oxytocin (OT)-deficient female mice produced by homologous recombination fail to lactate but exhibit normal parturition and reproductive behaviors. We examined the ultrasonic vocalizations of infant mice and the subsequent aggressive and fear behavior of adult male OT knockout (OT-KO) mice. Infant OT-KO mice were less vocal than wild-type (WT) control mice during separations from the mother and peers. Adult OT-KO males were generally more aggressive in isolation-induced and resident-intruder tests of aggression and less fearful in the plus maze and acoustic startle reflex tests than WT controls. Although the increase in tests of aggression was robust for OT-KO males from obligate litters (progeny of homozygous x homozygous crossings), the increase in aggression was reduced during tests for OT-KO males derived from nonobligate mating (progeny of heterozygous x heterozygous crossings), suggesting that the OT-KO genotype was not, by itself, responsible for the changes in adult behavior. We conclude that the absence of exposure to OT during development was associated with abnormalities in the development of emotional behavior.     

A novel mutant mouse, joggle, with inherited ataxia.

While establishing a new mouse strain, we discovered a novel mutant mouse that exhibited ataxia. Mating experiments showed that the mutant phenotype was due to a single autosomal recessive gene, which we have termed joggle (gene symbol: jog). The ataxia becomes apparent around postnatal day 12, when the mice first attempt to walk, and worsens thereafter. The life span of the mutant mouse is comparable to that of the wild-type mouse. After 21 days of age, the cerebellum weights of the jog/jog mice are significantly lower than those of the wild-type mice. These observations indicate that jog/jog mutant mice could be useful models for biomedical research.