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PubMed2003

Intracytoplasmic sperm injection (ICSI) enables rescue of valuable mutant mouse strains.

Genetically altered mice are important research tools for the study of human development and disease. Occasionally, whether or not related to the genetic mutation, mice may become infertile with age and, thus, risk loss of the mutant line. Under conditions in which assisted reproduction techniques (ARTs), such as in vitro fertilization, are unsuccessful, a new strategy, intracytoplasmic sperm injection (ICSI), may be applicable. This technique has been perfected for use in the mouse and is now considered a reliable, effective, and efficient ART. In the study reported here, we "rescued" (i.e., produced offspring, using ICSI from a "last-of-line" mutant male mouse) four lines that otherwise had become infertile and unresponsive to conventional ART's. A total of 26 live pups were produced from eight pregnant recipient foster mothers. Five mutant male mice were derived (one each from three lines, and two from one line), and all survived to adulthood. We found that live born mice could be successfully derived by use of ICSI that subsequently could breed by natural mating to reestablish the mutant line. Because of its effectiveness and reliability under these conditions, ICSI should be considered a powerful addition to the armamentarium of ART's applicable in the genetically-altered mouse, especially when only one male may still be available.

Animals↗
PubMed2002

The effect of a partial Y chromosome deletion in B10.BR-Ydel mice on testis morphology, sperm quality and efficiency of fertilization.

Males of the mouse strain B10.BR/SgSn and its congenic mutant strain B10.BR-Ydel, with a partial deletion of the Y chromosome, were used to examine factors related to poor sperm quality and quantity in the mutant strain. The testes of males from the two strains did not differ in their immunohistochemical reaction to androgen receptors or in the number of Sertoli and germ cells in tubules with normal morphology. However, mutants showed a greater frequency of degenerated tubules, a higher level of X-Y chromosome dissociation at meiosis (18% v. 10% in control males), and a lower content of resistant sperm heads in testis homogenates. In the cauda epididymidis, there was a higher percentage of spermatozoa with abnormal heads (88% v. 31%) and of spermatozoa with a cytoplasmic droplet still attached (74% v. 51%). Many sperm heads with flat acrosomes, occurring only in mutants (30% of sperm population), were deficient in proteolytic enzymes, as evidenced by the reaction on gelatine membranes. Most copulations of mutant males (11/18) were sterile in spite of the presence of spermatozoa in the uterus, but in the remaining copulations the fertilization rate was reasonably good (79%). Low numbers of spermatozoa were recovered from the oviducts, and those with the most severely deformed heads were less frequent there than in the uterus. The results show that a partial deletion of the Y chromosome affects efficiency of spermatogenesis, morphology of spermatozoa, their epididymal maturation and capacity to reach the ampulla and fertilize eggs.

Acrosome↗
PubMed2005

Alzheimer's disease-like neuropathology of gene-targeted APP-SLxPS1mut mice expressing the amyloid precursor protein at endogenous levels.

Most transgenic mice used for preclinical evaluation of potential disease-modifying treatments of Alzheimer's disease develop major histopathological features of this disease by several-fold overexpression of the human amyloid precursor protein. We studied the phenotype of three different strains of gene-targeted mice which express the amyloid precursor protein at endogenous levels. Only further crossing with transgenic mice overexpressing mutant human presenilin1 led to the deposition of extracellular amyloid, accompanied by the deposition of apolipoprotein E, an astrocyte and microglia reaction, and the occurrence of dilated cholinergic terminals in the cortex. Features of neurodegeneration, however, were absent. The pattern of plaque development and deposition in these mice was similar to that of amyloid precursor protein overproducing strains if crossed to presenilin1-transgenics. However, plaque development started much later and developed slowly until the age of 18 months but then increased more rapidly.

Alzheimer Disease↗
PubMed2001

Spontaneous loss-of-function mutations of the 8-oxoguanine DNA glycosylase gene in mice and exploration of the possible implication of the gene in senescence.

8-Oxoguanine is one of the major premutagenic oxidative base legions in vivo and is suspected to play a crucial role in various pathophysiological processes, such as cancer and aging. Mammalian 8-oxoguanine DNA glycosylase (OGG1) is thought to play a major role in the removal of 8-oxoguanine adducts in vivo. We have identified several inbred mouse strains with a spontaneous mutation, OGG1-R336H or double mutations, OGG1-R304W/R336H. R304W mutation caused a complete loss of OGG1 activity, while the R336H mutation led to disruption of nuclear localization of the enzyme although the activity remained normal. Among the double mutants was SAMP1, which exhibits accelerated senescence and short lifespan. We assessed the possible implication of the mutant OGG1 and 8-oxoguanine in aging utilizing SAMP1 mice. SAMP1 retained 1.5- to 1.9-fold increase in 8-oxoguanine level of hepatic nuclear DNA as compared with normal mice, until at least 12 months of age. A genetic association study, however, indicated that the mutant Ogg1 gene per se is not responsible for the accelerated senescence and short lifespan of SAMP1. Mutant OGG1 may be associated with pathologic conditions in other mouse strains.

Aging↗
PubMedDate not supplied

Murine models of renal disease: possibilities and problems in studies using mutant mice.

The elucidation of the pathogenesis of human renal disease at the molecular level has been facilitated by the growing field of gene targeting and the development of mouse strains with single-gene deletions - the 'knock-out' mice. Experimental nephrology, therefore, requires well-characterized and reliable models of human renal disease that can be induced reproducibly in mice. Today surgical procedures for the induction of renal ischemia, chronic renal failure, and ureter obstruction are feasible in mice. Models of mesangioproliferative or crescentic glomerulonephritis, glomerulosclerosis, and tubulointerstitial disease are readily available; however, these depend heavily on the mouse genetic background. Attention to the genetic background and appropriate backcrossing are, therefore, of great importance in the design and interpretation of experimental studies, especially in transgenic mice. Simple murine models displaying the clinical features of other human renal diseases such as IgA nephropathy, membranous glomerulonephritis, and renal vasculitis are still lacking. Mouse strains that spontaneously develop distinct renal pathologies similar to lupus nephritis and focal-segmental glomerulosclerosis can be intercrossed with transgenic mice to study the impact of single-gene deletions on the renal phenotype. The present review provides a survey about currently available spontaneous and inducible murine models of renal disease with special attention to problems and future perspectives for their use in transgenic animals.

Acute Kidney Injury↗
PubMed1999

Genetics of mouse behavior: interactions with laboratory environment.

Strains of mice that show characteristic patterns of behavior are critical for research in neurobehavioral genetics. Possible confounding influences of the laboratory environment were studied in several inbred strains and one null mutant by simultaneous testing in three laboratories on a battery of six behaviors. Apparatus, test protocols, and many environmental variables were rigorously equated. Strains differed markedly in all behaviors, and despite standardization, there were systematic differences in behavior across labs. For some tests, the magnitude of genetic differences depended upon the specific testing lab. Thus, experiments characterizing mutants may yield results that are idiosyncratic to a particular laboratory.

Animals↗
PubMed2006

Regulation of insulin secretion and beta-cell mass by activating signal cointegrator 2.

Activating signal cointegrator 2 (ASC-2) is a transcriptional coactivator of many nuclear receptors (NRs) and other transcription factors and contains two NR-interacting LXXLL motifs (NR boxes). In the pancreas, ASC-2 is expressed only in the endocrine cells of the islets of Langerhans, but not in the exocrine cells. Thus, we examined the potential role of ASC-2 in insulin secretion from pancreatic beta-cells. Overexpressed ASC-2 increased glucose-elicited insulin secretion, whereas insulin secretion was decreased in islets from ASC-2+/- mice. DN1 and DN2 are two dominant-negative fragments of ASC-2 that contain NR boxes 1 and 2, respectively, and block the interactions of cognate NRs with the endogenous ASC-2. Primary rat islets ectopically expressing DN1 or DN2 exhibited decreased insulin secretion. Furthermore, relative to the wild type, ASC-2+/- mice showed reduced islet mass and number, which correlated with increased apoptosis and decreased proliferation of ASC-2+/- islets. These results suggest that ASC-2 regulates insulin secretion and beta-cell survival and that the regulatory role of ASC-2 in insulin secretion appears to involve, at least in part, its interaction with NRs via its two NR boxes.

Amino Acid Motifs↗
PubMed1983

Adherent cell growth from murine bone marrow in liquid cultures. Inbred strain variability and effects of mutations affecting hemopoiesis.

The marrow cells of mice from seven hematologically normal strains (AKR/J, AKR/Cum, CBA/J, C3H/HeJ, C57B1/6J, DBA/2J, and RF/J) and of mice with five mutations in loci affecting hemopoiesis (W, Sl, nu, xid, NZB) were tested. The following parameters of adherent cell growth in 14 day liquid culture were analyzed: number and diameter of macroscopic adherent colonies, cellular composition with particular reference to the number of macrophage-like cells attached to a single fibroblast-like cell on peripheries of adherent colonies and the number of macrophage-like cells per eyefield of intercolony spaces. No qualitative differences were observed between tested genotypes in the cellular composition of adherent layers. These layers were uniformly made of colonies of fibroblast-like cells that were overgrown by macrophage-like cells. Macrophage-like cells grew also in intercolony spaces but this never occurred to fibroblast-like cells. At least using light microscopy and Wright's staining no morphological differences could be observed between either fibroblast-like cells or macrophage-like cells derived from marrow of various murine strains. This is of particular significance for Sl/Sld mice that suffer from the functional defect of hemopoietic microenvironment. On the other hand, large strain variability was observed in the number (5-16/10(6) marrow cells, 10.6 on the average) and diameter (1.9-3.7 mm, 2.9 mm on the average) of macroscopic adherent colonies. Among mutant genotypes, only NZB mice and animals with xid mutation formed significantly increased numbers of macroscopic colonies, while values for other mutant genotypes, Sl/Sld included, did not differ from normal littermate controls.

Animals↗
PubMed2002

Angptl3 regulates lipid metabolism in mice.

The KK obese mouse is moderately obese and has abnormally high levels of plasma insulin (hyperinsulinemia), glucose (hyperglycemia) and lipids (hyperlipidemia). In one strain (KK/San), we observed abnormally low plasma lipid levels (hypolipidemia). This mutant phenotype is inherited recessively as a mendelian trait. Here we report the mapping of the hypolipidemia (hypl) locus to the middle of chromosome 4 and positional cloning of the autosomal recessive mutation responsible for the hypolipidemia. The hypl locus encodes a unique angiopoietin-like lipoprotein modulator, which we named Allm1. It is identical to angiopoietin-like protein 3, encoded by Angptl3, and has a highly conserved counterpart in humans. Overexpression of Angptl3 or intravenous injection of the purified protein in KK/San mice elicited an increase in circulating plasma lipid levels. This increase was also observed in C57BL/6J normal mice. Taken together, these data suggest that Angptl3 regulates lipid metabolism in animals.

Amino Acid Sequence↗
PubMed1981

[Regulation of the intensity of delayed-type hypersensitivity to sheep erythrocytes by the K-region of the major histocompatibility complex in mice].

The injection of 6 x 10(9) sheep red blood cells (SRBC) to mice suppressed the delayed type hypersensitivity (DTH) in situ and activated spleen T cells which prevent sensitization of syngeneic recipients. Similar effect was obtained when suppressor cells induced in F1 hybrids were transferred to parental mice. Suppression was also reached in allogeneic strain combination if suppressor cells of donors and recipients shared the major histocompatibility complex (MHC). Studied performed with recombinant and mutant strains revealed that the prerequisite for interaction of DTH suppressors and effectors was the identity of K-region of MHC. Passive transfer of DTH to SRBC was also possible if donors and recipients were identical in K-region of MHC. It is believed that interaction between DTH suppressors and effectors is restricted by a region of MHC whose product takes part in antigen representation.

Animals↗
PubMed1981

Prevention of changes after UV-irradiation by sunscreen products in skin of hairless mice.

Female hairless mice (strain mutant hr/hr) have been irradiated with increasing doses of UV-B over a period of 4 weeks. They were compared with untreated controls Additional groups of 30 mice were treated with milk base or cream base or milk SPF6 or cream SPF6 or cream SPF8 daily before irradiation. No changes of body weight indicating systemic effects were found. Skin thickness was increased significantly after irradiation. These changes were partially antagonized by cream or milk bases and completely prevented by the corresponding formulations containing sunscreen agents. Under the chosen conditions ultimate load of excised skin samples was increased by irradiation. This effect was not reversed by the bases but by the sunscreen products. Ultimate strain of excised skin samples proved to be the most sensitive indicator. The decrease of ultimate strain after irradiation was partially antagonized by the bases. The sunscreen products had more powerful effect. Due to the effects on skin thickness and ultimate load tensile strength and modulus of elasticity did not show significant changes under the chosen conditions. Likewise, collagen and elastin content per gram wet weight did not show significant changes. Considering the increase of thickness of skin which is prevented by sunscreen products one may conclude also a prevention of formation of additional intercellular material. The results prove the value of sunscreen products. Furthermore, they demonstrate a new method for evaluation of chemicals and sun protection preparations.

Animals↗
PubMed1998

Dominant lethality of the mouse skeletal mutation tail-short (Ts) is determined by the Ts allele from mating partners.

Mice with the Tail-short (Ts) mutation have a short, kinky tail and numerous skeletal abnormalities, including a homeotic anteroposterior patterning problem involving the axial skeleton. The viability of Ts heterozygotes varies dramatically, depending on the mouse strain crossed with the mutant strain. At the extremes, the heterozygotes are viable or lethal prenatally. In this study, we found that laboratory mouse strains could be divided into two groups. A cross with strains from the first group yielded viable Ts heterozygotes, whereas a cross with the second group resulted in dominant lethality in utero. We planned to map the gene(s) that controls strain differences in the viability of the Ts heterozygotes. The result clearly indicated that a single chromosomal region, genetically inseparable from the Ts locus, is responsible for these differences. This suggests that allelism at the Ts locus generates variable manifestation of the mutant phenotype. Morphological and histological analyses indicated that embryos from the lethal cross exhibit severe developmental defects from the gastrulation stage through the early fetal stage. In particular, the umbilical vein does not develop properly. All of these results suggest that the phenotype of the Ts mutant is modified by the Ts alleles of the mating partners.

Alleles↗
PubMed1990

Acetylcholinesterase-positive innervation in cochleas from two strains of shaker-1 mice.

Shaker-1 is a recessive gene mutation on chromosome 7 in mice, causing both deafness and neurosensory degeneration in the inner ear. A failure of efferent innervation to the outer hair cells is being implicated in the cause of deafness (Green, 1981). To investigate the efferent innervation, we examined the cochleas of two strains of shaker-1 mutants: Sh1/Le (25 and 45 days old) and FS/Ei (28 and 68 days old), using enzymatic staining of acetylcholinesterase (AChE) for the light and electron microscopes, and also by measuring the activities of AChE and of AChE molecular forms. The enzyme levels in the SH1/Le and FS/Ei homozygotes (sh-1/sh-1) were within the range of those in SH1/Le heterozygotes (+/sh-1) and in normal mouse strains (C3H/HeJ, 129/SvJ, ICR). The picture of AChE-positive innervation in both strains differed. In the SH1/Le mutants at 25 days, the innervation appeared normal, but by 45 days it showed a marked atrophy. In the FS/Ei mutants, the degeneration was already evident by the 28th day. In the younger animals of both mutants, large differentiated vesiculated nerve endings were ultrastructurally detected in synaptic contact with outer hair cells. The preservation of AChE activity and of the expression of AChE molecular forms up to 68 days indicate that the shaker-1 cochlea may initially possess a normal input of AChE-positive efferent innervation. The late onset and the slow course of the degeneration of AChE-positive innervation seen in the SH1/Le mutants suggest that the loss of efferent endings may be, contrary to previous suggestions, the consequence rather than the cause of the shaker-1 pathology.

Acetylcholinesterase↗
PubMed1997

Isolated maxillary bending in CL/FR strain mice: observation of craniofacial deformity and inheritance pattern.

OBJECTIVE: The CL/Fr mouse, known as a strain with spontaneous cleft lip and/or palate (CL/P), has been used as an animal model to investigate etiology in CL/P. METHOD: We examined a facial asymmetry mutant discovered in a CL/Fr mouse colony that was not associated with CL/P and was shown to be inheritable in subsequent generations. Facial asymmetry became apparent with postnatal growth, whereas it was not detectable at birth, and was termed "maxillary bending" (MB) based on the characteristic bending of the maxilla. RESULTS: As a result of selective breeding, an 'MB line', In which MB was observed in 21.68% (67/309) in addition to CL/P in 17.80% (55/309) of the offspring, was developed in the CL/Fr colony. In mating experiments between the MB line and C57BL/6J, all F1 progeny showed the normal phenotype. MB was observed in 0.72% (1/139) of the F2 generation, and the backcross generation showed segregation of MB in 6.25% (22/352) and CL/P in 1.42% (5/352). These instances suggested the occurrence of an additional mutation in the CL/Fr mouse genome controlled by an autosomal recessive gene with low penetrance. However, since the CL/Fr mouse primarily has a developmental deficiency in the maxilla, the possibility that CL/P and MB share common etiologic factors cannot be completely ruled out. CONCLUSION: The maxillary bending retains significance, as this mutant can serve as an animal model of abnormal facial growth. Elucidation of the etiologic relationship between MB and CL/P may provide clues to clarifying the deficiency in first branchial arch in the mouse.

Animals↗
PubMed1998

Nickel subsulfide is genotoxic in vitro but shows no mutagenic potential in respiratory tract tissues of BigBlue rats and Muta Mouse mice in vivo after inhalation.

Carcinogenic nickel compounds are known to induce promutagenic DNA lesions such as DNA strand breaks and DNA adducts in cultured mammalian cells. In standard mutation assays, in contrast, they were found to be either inactive or weakly active. In our in vitro mutation studies in a lacI transgenic embryonic fibroblast cell line, nickel subsulfide (Ni3S2) increased mutation frequency up to 4. 5-fold. We subsequently applied the comet assay and transgenic rodent mutation assays to investigate the DNA damaging effect and mutagenic potential of nickel subsulfide in target cells of carcinogenesis. A 2-h in vitro treatment of freshly isolated mouse nasal mucosa and lung cells with nickel subsulfide clearly induced DNA fragmentation in a concentration dependent manner. The strong effect was not seen in the same cell types following inhalative treatment of mice and rats, leading only in the mouse nasal mucosa to high DNA damage. When the same inhalative treatment was applied to lacZ and lacI transgenic mice and rats, the spontaneous mutation frequency of these target genes in the respiratory tissues was not increased. These results support a recently proposed non-genotoxic model of nickel carcinogenesis, which acts through gene silencing via DNA methylation and chromatin condensation. This model may also explain our in vitro mutation data in the lacI transgenic cell line, in which nickel subsulfide increased mutation frequency, but in about one-third of the mutants, molecular analysis did not reveal any DNA sequence change in the coding region of the lacI gene despite of the phenotypic loss of its function.

Administration, Inhalation↗