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PubMed1996

Immunologic basis of transplant-associated arteriosclerosis.

Although immunosuppressive therapy minimizes the risk of graft failure due to acute rejection, transplant-associated arteriosclerosis of the coronary arteries remains a significant obstacle to the long-term survival of heart transplant recipients. The participation of specific inflammatory cell types in the genesis of this lesion was examined in a mouse model in which carotid arteries were transplanted across multiple histocompatibility barriers into seven mutant strains with immunologic defects. An acquired immune response--with the participation of CD4+ (helper) T cells, humoral antibody, and macrophages--was essential to the development of the concentric neointimal proliferation and luminal narrowing characteristic of transplant arteriosclerosis. CD8+ (cytotoxic) T cells and natural killer cells were not involved in the process. Arteries allografted into mice deficient in both T-cell receptors and humoral antibody showed almost no neointimal proliferation, whereas those grafted into mice deficient only in helper T cells, humoral antibody, or macrophages developed small neointimas. These small neointimas and the large neointimas of arteries grafted into control animals contained a similar number of inflammatory cells; however, smooth muscle cell number and collagen deposition were diminished in the small neointimas. Also, the degree of inflammatory reaction in the adventitia did not correlate with the size of the neointima. Thus, the reduction in neointimal size in arteries allografted into mice deficient in helper T cells, humoral antibody, or macrophages may be accounted for by a decrease in smooth muscle cell migration or proliferation.

Animals↗
PubMed2001

Genetically engineered mice and their use in aging research.

Genetically engineered animal models have been and will continue to be invaluable for exploring the basic mechanisms involved in the aging process as well as in extending our understanding of diseases found to be more prevalent in the older human population. Continued development of such in vivo systems will allow scientists to further dissect the role genetic and environmental factors play in aging and in age-related disease states and to enhance our understanding of these processes. In this article we discuss techniques involved in the development of such models and review some examples of laboratory mouse strains that have been used to study either normal aging or select diseases associated with aging.

Aging↗
PubMed1986

[Expression of mutant eyeless genes in the mouse embryo retina].

The aim of the present study was to determine the cellular site of eyeless-I (ey-I) and eyeless-2 (ey-2) gene action, causing anophthalmia or microphthalmia. Eye primordia from 10-day-old embryos of ZRDCT-AN and CC57BR (control) mice were cultured in vitro for 3 or 6 days. In 59 out of 77 cultured mutant eye primordia neural retina was disturbed. In 9 mutant eye primordia the disturbed neural retina was 4-6 times thinner than in the control. However, lens differentiation was similar to that in the control, epithelial and fibrous components were observed. Thus, mutant genes eyeless inhibit the growth of primordial retina, causing secondary developmental defects of the lens and other eye structures.

Animals↗
PubMed1982

Defective thyroid ontogenesis in fetal hypothyroid (hyt/hyt) mice.

Thyroid glands of fetal hypothyroid (hyt/hyt) mice were studied to determine the effects of the mutant gene during embryogenesis. Comparisons of mutant and normal thyroids were made with respect to morphology, iodine-concentrating ability, and glandular thyroxine (T4) content at day 18 of gestation. Fetal hyt/hyt thyroid tissue was properly located, but incompletely differentiated. The mutant thyroid was characterized microscopically by small, poorly developed follicles with colloid diminished in PAS-staining properties. The mutant glands' ability to concentrate iodine was found to be only 5--16% of that exhibited by normal glands. When litters contained both mutant and normal off-spring, the differential iodine-concentrating ability allowed fetuses to be separated into two distinct, nonoverlapping populations. The distribution of fetal mice into high or low iodine-concentrating groups agreed closely with predicted frequencies for normal and mutant phenotypes. Thyroid content of T4 in mutant mice was found to be approximately equal to that found in age-matched normal controls. The poorly developed morphology and deficient iodine-concentrating ability of fetal thyroids from day 18 hyt/hyt mice indicated that the mutant gene acts during the ontogeny of this gland. Although such data are not available on human fetuses affected by thyroid dysgenesis, postnatal hyt/hyt mice display characteristics similar to those of infants born with this form of congenital primary hypothyroidism. Thus, elucidation of the site of mutant gene action in the mouse should contribute to our knowledge of disturbed fetal thyroid development and its implications in the adult mammal.

Animals↗
PubMed1998

The level of CD4 surface protein influences T cell selection in the thymus.

During T cell development thymocytes are subjected to positive and negative selection criteria to ensure that the mature T cell repertoire is MHC restricted, yet self tolerant at the same time. The CD4 and CD8 coreceptors are thought to play a crucial role in this developmental process. To elucidate the role of CD4 in T cell selection, we have produced a mouse strain that expresses CD4 at a reduced level. We used homologous recombination in embryonic stem cells to insert neo into the 3' untranslated region of CD4. The resulting mice have a reduction in the percentage of CD4+ cells in the thymus and a concomitant increase in CD8+ cells. In addition, breeding two individual class II-restricted TCR transgenic mice onto the CD4low (low level of CD4) mutant background affects the selection of each TCR differentially. In one case (AND TCR transgenic), significantly fewer CD4+ cells with the transgenic TCR develop on the CD4low mutant background, whereas in the other (5C.C7 TCR transgenic), selection to the CD4 lineage is only slightly reduced. These data support the differential avidity model of positive and negative selection. With little or no avidity, the cell succumbs to programmed cell death, low to moderate avidity leads to positive selection, and an avidity above a certain threshold, presumably above one that would lead to autoreactivity in the periphery results in clonal deletion. These data also support the idea that a minimum avidity threshold for selection exists and that CD4 plays a crucial role in determining this avidity.

Animals↗
PubMed1998

A point mutation in the neu-1 locus causes the neuraminidase defect in the SM/J mouse.

Lysosomal neuraminidase (sialidase) occurs in a high molecular weight complex with the glycosidase beta-galactosidase and the serine carboxypeptidase protective protein/cathepsin A (PPCA). Association of the enzyme with PPCA is crucial for its correct targeting and lysosomal activation. In man two genetically distinct storage disorders are associated with either a primary or a secondary deficiency of lysosomal neuraminidase: sialidosis and galactosialidosis. In the mouse the naturally occurring inbred strain SM/J presents with a number of phenotypic abnormalities that have been attributed to reduced neuraminidase activity. SM/J mice were originally characterized by their altered sialylation of several lysosomal glycoproteins. This defect was linked to a single gene, neu-1 , on chromosome 17, which was mapped by linkage analysis to the H-2 locus. In addition, these mice have an altered immune response that has also been coupled to a deficiency of the Neu-1 neuraminidase. Here we report the identification in SM/J mice of a single amino acid substitution (L209I) in the Neu-1 protein which is responsible for the partial deficiency of lysosomal neuraminidase. We propose that the reduced activity is caused by the enzyme's altered affinity for its substrate, rather than a change in substrate specificity or turnover rate. The mutant enzyme is correctly compartmentalized in lysosomes and maintains the ability to associate with its activating protein, PPCA. We propose that it is this mutation that is responsible for the SM/J phenotype.

Adenosine Diphosphate↗
PubMed1998

Mouse models for extracellular matrix diseases.

Mutations of a number of genes encoding for extracellular matrix (ECM) proteins in mice have provided new insights regarding their role during development and disease. Many mouse strains have helped to verify the link between mutation and disease in humans, and others have produced unexpected phenotypes and identified new functions for ECM proteins. Finally, some null mutations in ECM genes provide no phenotypic alterations in mice, confronting the scientific community with a new challenge to search for their functions. This review lists all mouse strains with spontaneous and experimentally induced mutations in ECM genes. The phenotypes of these mice are discussed in comparison with the human diseases.

Animals↗
PubMed2006

Mice mutant in the DM domain gene Dmrt4 are viable and fertile but have polyovular follicles.

Proteins containing the DM domain, a zinc finger-like DNA binding motif, have been implicated in sexual differentiation in diverse metazoan organisms. Of seven mammalian DM domain genes, only Dmrt1 and Dmrt2 have been functionally analyzed. Here, we report expression analysis and targeted disruption of Dmrt4 (also called DmrtA1) in the mouse. Dmrt4 is widely expressed during embryonic and postnatal development. However, we find that mice homozygous for a putative null mutation in Dmrt4 develop essentially normally, undergo full sexual differentiation in both sexes, and are fertile. We observed two potential mutant phenotypes in Dmrt4 mutant mice. First, ovaries of most mutant females have polyovular follicles, suggesting a role in folliculogenesis. Second, 25% of mutant males consistently exhibited copulatory behavior toward other males. We also tested potential redundancy between Dmrt4 and two other gonadally expressed DM domain genes, Dmrt1 and Dmrt7. We observed no enhancement of gonadal phenotypes in the double mutants, suggesting that these genes function independently in gonadal development.

Animals↗
PubMed1997

Giant renin secretory granules in beige mouse renal afferent arterioles.

The mutant beige mouse (C57BL/6 bg) has a disease characterised by abnormally enlarged cytoplasmic granules in a variety of cells. With the purpose of establishing a suitable cellular model for studying renin secretion, the present study was undertaken to compare renin granule morphology in beige mice with that of control (NMRI) mice. Immunohistochemistry with an antibody specific for renin revealed intense staining of the juxtaglomerular part of the afferent arterioles in both strains of mice. Plasma renin concentrations were higher in the controls than in the beige mice (4.4+/-0.6 vs 2.5+/-0.3 mGoldblatt units/ml). The total volume of renin granules per afferent arteriole was similar in the two mice strains (1114 microm3 in the controls and 1507 microm3 in the beige mice). The total number of renin granules per arteriole as assessed by stereological techniques was about 1900 in controls (average granular volume 0.681 microm3), whereas 1-2 large granules were present per cell in beige mice. The volume of afferent arteriole that contained secretory granules was lower in the beige mice. We conclude that the beige mouse synthesizes, stores and releases active renin. Renin secretory granules in beige mice are grossly enlarged with 1-2 granules per juxtaglomerular cell. Compared with control mice, a similar amount of total renin granule volume per afferent arteriole is contained in a smaller part of beige mouse afferent arteriole. Granular cells from beige mice could therefore be a valuable tool in the study of renin release.

Animals↗
PubMedDate not supplied

Immune competence involving the natural killer cell lineage promotes placental growth.

Very small placentae and absence of uterine natural killer (uNK) cells are amongst the reproductive deficits found in the natural killer (NK) cell and thymus-derived (T) cell immunodeficient mouse tgepsilon26. These defects can be reversed by grafting of adult tgepsilon26 females with bone marrow from T and B cell immunodeficient scid/scid donors. We report here that a second protocol, grafting of neonatal tgepsilon26 females with immunocompetent bone marrow pretreated with antibody to Thy-1, successfully established the uNK cell lineage and ameliorated the phenotype. Further, comparisons of mid-gestation (days 10-16) placental area measurements from tgepsilon26 and seven other immunodeficient strains to time-matched tissues from four strains of immunocompetent mice indicate that lymphocytes of the NK but not the T or B cell lineages are able to influence placental size during normal gestation and that this action is independent of interleukin 2. Area measurements of placentae produced in manipulated tgepsilon26 pregnancies (maternal bone marrow engraftment, outcrossing to immunocompetent males and reciprocal embryo transfers with an immunocompetent strain) suggest that NK cell competence is required in each of the maternal and fetal compartments to optimize placental growth.

Animals↗
PubMed1998

Mapping a gene for combined hyperlipidaemia in a mutant mouse strain.

Familial combined hyperlipidaemia (FCHL) is a common, multifactorial disorder associated with elevated levels of plasma triglyceride, cholesterol, or both. A characteristic feature is increased secretion of very low density lipoproteins (VLDL) and apolipoprotein B (apoB). Although FCHL is the most common cause of premature coronary artery disease (CAD), accounting for over 10% of cases, its aetiology remains largely unknown. One powerful approach to the dissection of complex genetic traits involves the use of animal models. We have identified a mouse strain, HcB-19/Dem (HcB-19), which exhibits hypertriglyceridaemia, hypercholesterolaemia and elevated levels of plasma apoB. Like FCHL patients, HcB-19 mice also exhibit increased secretion of triglyceride-rich lipoproteins, and their hyperlipidaemia becomes progressively more severe with age. It is likely that the hyperlipidaemia results from a mutation of a novel gene that arose during development of strain HcB-19. We mapped the hyperlipidaemia gene (Hyplip1) to the distal portion of mouse chromosome 3. This region is syntenic to human chromosome 1q21-q23, which has recently been shown to harbour a gene associated with FCHL in families from a Finnish isolate.

Age Factors↗
PubMed2000

Dorsal patterning defects in the hindbrain, roof plate and skeleton in the dreher (dr(J)) mouse mutant.

dreher is a spontaneous mouse mutation in which adult animals display a complex phenotype associated with hearing loss, neurological, pigmentation and skeletal abnormalities. During early embryogenesis, the neural tube of dreher mutants is abnormally shaped in the region of the rhomboencephalon, due to problems in the formation of a proper roof plate over the otic hindbrain. We have studied the expression of Hox/lacZ transgenic mouse strains in the dreher background and shown that primary segmentation of the neural tube is not altered in these mutants, although correct morphogenesis is affected resulting in misshapen rhombomeres. Neural crest derivatives from rhombomere 6, such as the glossopharyngeal ganglion, are defective, and the dorsal neural tube marker Wnt1 is absent from this segment. Selected trunk neural crest populations are also altered, as there is a lack of pigmentation in the thoracic region of mutant mice. Skeletal defects include abnormal cranial bones of neural crest origin, and improper fusion of the dorsal aspects of cervical and thoracic vertebrae. Taken together, the gene affected in the dreher mutant is responsible for correct patterning of the dorsal-most cell types of the neural tube, that is, the neural crest and the roof plate, in the hindbrain region. Axial skeletal defects could reflect inductive influence of the dorsal neural tube on proper fusion of the neural arches. It is possible that a common precursor population for both neural crest and roof plate is the cellular target of the dreher mutation.

Animals↗
PubMed2004

Differences in the embryonic expression patterns of mouse Foxf1 and -2 match their distinct mutant phenotypes.

Murine genes encoding the forkhead transcription factors Foxf1 and -2 are both expressed in derivatives of the splanchnic mesoderm, i.e., the mesenchyme of organs derived from the primitive gut. In addition, Foxf2 is also expressed in limbs and the central nervous system. Targeted mutagenesis of Foxf1 and -2 suggests that Foxf1 is the more important of the two mammalian FoxF genes with early embryonic lethality of null embryos and a haploinsufficiency phenotype affecting foregut-derived organs. In contrast, the only reported defect in Foxf2 null embryos is cleft palate. To investigate if the differences in mutant phenotype can be attributed to nonoverlapping expression patterns or if distinct functions of the encoded proteins have to be inferred, we analyzed the early embryonic expression of Foxf2 and compared it with that of the better investigated Foxf1. We find that in the early embryo, Foxf1 is completely dominating-in terms of expression-in extraembryonic and lateral plate mesoderm, consistent with the malformations and early lethality of Foxf1 null mutants. Along the developing gut, Foxf1 is highly expressed throughout, whereas Foxf2 expression is concentrated to the posterior part-fitting the foregut haploinsufficiency phenotypes of Foxf1 mutants. Foxf2, on the other hand, is more prominent than Foxf1 in mesenchyme around the oral cavity, as would be predicted from the cleft palate phenotype. The differences in expression pattern also highlight areas where defects should be sought for in the Foxf2 mutant, for example limbs, the posterior gut, genitalia, and derivatives of the neural crest mesenchyme.

Animals↗
PubMed1985

Genetic resistance to murine cryptococcosis: the beige mutation (Chédiak-Higashi syndrome) in mice.

The influence of the bgJ and bg2J mutations on the susceptibility of mice to experimental cryptococcosis was studied in inbred mice of the C57BL/6J and C3H/HeJ strains. Although infected animals with the bg/bg genotype had a significantly shorter lifespan than bg/+ or +/+ animals, C3H/He beige-2J mice were less susceptible than C57BL/6 beige-J mice when compared with nonbeige mice of similar background. On days 18 and 19 after infection, quantitation of cryptococci in the brain, liver, and spleen revealed that the overall burden of organisms in infected C57BL/6 beige-J mice was in excess of one log unit above that found in the brain, liver, and spleen of infected C57BL/6 +/+ mice. At that time, C57BL/6 beige-J mice showed a 53% increase in mean brain weight, a 67.8% decrease in mean liver weight, and a 58.6% decrease in mean spleen weight, when compared with uninfected animals of the same age and genetical lineage. The corresponding figures for C57BL/6 +/+ mice were a 32% increase in mean brain weight, a 41.4% decrease in mean liver weight, and a 23.4% decrease in mean spleen weight. From these data, it is concluded that the beige mutation in mice is associated with increased susceptibility to cryptococcosis, the accrued susceptibility of the beige mutant is related to more rapid changes in the weight profile of the target organs as well as to a higher rate of growth or decreased clearance of Cryptococcus neoformans or both, and other autosomal genes are likely to be involved in the genetic control of susceptibility to murine cryptococcosis.

Animals↗
PubMed2000

Xenogeneic transplantation of human spermatogonia.

In the last 3 years, several studies have shown that xenogeneic transplantation of rodent spermatogonia is feasible. The treatment of infertile patients with spermatogenic arrest using the injection of immature germ cells has yielded only poor results. We attempted to establish a complete spermatogenetic line in the testes of mutant aspermatogenic (W/Wv) and severe combined immunodeficient mice (SCID) transplanted with germ cells from azoospermic men. Spermatogenic cells were obtained from testicular biopsy specimens of men (average age of 34.3 +/- 9 years) undergoing infertility treatment because of obstructive and non-obstructive azoospermia. Testicular tissue was digested with collagenase to promote separation of individual spermatogenic cells. The germ cells were injected into mouse testicular seminiferous tubules using a microneedle (40 microm inner diameter) on a 10 ml syringe. To assess the penetration of the cell suspension into the tubules, trypan blue was used as an indicator. Mice were maintained for 50 to 150 days to allow time for germ cell colonisation and development prior to them being killed. Testes were then fixed for histological examination and approximately 100 cross-sectioned tubules were examined for human spermatogenic cells. A total of 26 testicular cell samples, 16 frozen and 10 fresh, were obtained from 24 men. The origin of the azoospermia was obstructive (OA) in 16 patients and non-obstructive (NOA) in 8 patients. The concentration of spermatogenic cells in the OA group was 6.6 x 10(6) cells/ml, and 1.3 x 10(6) cells/ml in the NOA group (p < 0.01). The different spermatogenic cell types were distributed equally in the OA samples, ranging from spermatogenia to fully developed spermatozoa, but in the NOA group the majority of cells were spermatogonia and spermatocytes. A total of 23 testes from 14 W/Wv mice and 24 testes from 12 SCID mice were injected successfully, as judged by the presence of spermatogenic cells in histological sections of testes removed immediately after the injection. However, sections from the remaining testes examined up to 150 days after injection showed tubules lined with Sertoli cells and xenogeneic germ cells were not found. The reason why the two strains of mouse used as recipients did not allow the implantation of human germ cells is probably due to interspecies specificity involving non-compatible cell adhesion molecules and/or immunological rejection.

Adult↗
PubMed2000

Formation of the definitive endoderm in mouse is a Smad2-dependent process.

TGFbeta growth factors specify cell fate and establish the body plan during early vertebrate development. Diverse cellular responses are elicited via interactions with specific cell surface receptor kinases that in turn activate Smad effector proteins. Smad2-dependent signals arising in the extraembryonic tissues of early mouse embryos serve to restrict the site of primitive streak formation and establish anteroposterior identity in the epiblast. Here we have generated chimeric embryos using lacZ-marked Smad2-deficient ES cells. Smad2 mutant cells extensively colonize ectodermal and mesodermal populations without disturbing normal development, but are not recruited into the definitive endoderm lineage during gastrulation. These experiments provide the first evidence that TGFbeta signaling pathways are required for specification of the definitive endoderm lineage in mammals and identify Smad2 as a key mediator that directs epiblast derivatives towards an endodermal as opposed to a mesodermal fate. In largely Smad2-deficient chimeras, asymmetric nodal gene expression is maintained and expression of pitx2, a nodal target, is also unaffected. These results strongly suggest that other Smad(s) act downstream of Nodal signals in mesodermal populations. We found Smad2 and Smad3 transcripts both broadly expressed in derivatives of the epiblast. However, Smad2 and not Smad3 mRNA is expressed in the visceral endoderm, potentially explaining why the primary defect in Smad2 mutant embryos originates in this cell population.

Animals↗
PubMed1990

All-or-none craniorachischisis in Loop-tail mutant mouse chimeras.

Mouse embryos homozygous for the mutant gene Loop-tail (Lp) are characterized by craniorachischisis, an open neural tube extending from the midbrain to the tail. In the present study, experimental chimeric mice containing mixtures of genetically mutant (from Lp/+ x Lp/+ matings) and genetically normal cells were produced. Our aim was to determine whether a 'rescue,' phenotypic gradient, or intermediate expression (i.e. alternating areas of open and closed neural tube) would be observed in these chimeras. We report our analyses of Loop-tail mutant chimeras (n = 82) by gross examination, progeny testing and quantitative analysis of glucose phosphate isomerase (GPI) isozyme levels. An all-or-none craniorachischisis in Loop-tail mutant chimeras was observed. Two multicolored adult chimeras, without any gross evidence of a neural tube defect, were shown to be homozygous Loop-tail chimeras (Lp/Lp in equilibrium +/+) by progeny testing. These results indicate that the normal phenotype can be expressed in the presence of mutant cells. Conversely, six neonates with craniorachischisis were shown to be chimeras by GPI analyses. These results show that the full mutant phenotype can be expressed even when one-third to one-half of the cells are genotypically wild-type. This study did not determine which tissue is primarily responsible for the defective neurulation in this mutant, but suggests that a 'threshold' mechanism underlies the Loop-tail mutant phenotype. In some chimeras that threshold is not reached and the neural tube remains open, whereas in other chimeras the threshold is reached and the neural tube closes completely.

Animals↗
PubMed1999

Targeted inactivation of Hoxb8 affects survival of a spinal ganglion and causes aberrant limb reflexes.

Hoxb8 mutant mice were generated by inserting the lacZ coding sequence in frame with the first exon of Hoxb8. These mice express a fusion protein with a functional beta-galactosidase activity instead of Hoxb8. Mutant embryos were analyzed for anatomical changes. The results indicate that Hoxb8 is not an indispensable regulator of A-P patterning in the forelimb, unlike suggested by our Hoxb8 gain of function experiments (Charité J, DeGraaff W, Shen S, Deschamps J. Cell 1994;78:589-601). The null mutant phenotypic traits include degeneration of the second spinal ganglion (C2), an abnormality opposite to the alteration in the gain of function transgenic mice. Subtle changes in the thoracic part of the vertebral column were observed as well. Adult homozygous mutants exhibit an abnormal clasping reflex of the limbs.

Animals↗