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PubMed1984

Histologic changes produced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the skin of mice carrying mutations that affect the integument.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) produces epidermal hyperplasia and hyperkeratosis, squamous metaplasia of the sebaceous gland, and keratinized cyst formation in 8 strains of mice with the recessive mutation, hairless (hr/hr). The extent of these histologic changes is dependent on the genetic background. No cutaneous lesions are produced in haired (hr/+) mice. In examination of mice with 7 other mutations affecting the integument, TCDD produced similar histologic skin changes in cryptothrix, nude, plucked, and atrichosis; a marginal squamous metaplasia of sebaceous glands in Repeated epilation, and had no effect in fur deficient and Naked mutants. These genetically determined epidermal responses are discussed in light of the mechanism of action of TCDD.

Alleles↗
PubMed1984

Effect of genetic background on the therapeutic effects of dehydroepiandrosterone (DHEA) in diabetes-obesity mutants and in aged normal mice.

Dehydroepiandrosterone (DHEA) was fed at 0.1-0.4% in the diet to genetically diabetic (db/db) or obese (ob/ob) C57BL/KsJ (BL/Ks) or C57BL/6J (BL/6) mice. Treatment of BL/Ks-db/db or ob/ob mice with 0.4% DHEA prevented hyperglycemia, islet atrophy, and severe diabetes associated with this inbred background, but did not affect weight gain and food consumption. Homozygous obese (ob) or diabetes (db) mice on the BL/6 background were more sensitive to DHEA, and the mild, transient hyperglycemia associated with ob or db gene expression on the BL/6 inbred background could be prevented by 0.1% DHEA. Both body weight and food consumption were decreased in BL/6 mutants maintained on 0.1% DHEA whereas this effect was not seen in BL/Ks mutants fed up to 0.4% DHEA. Early therapy with 0.4% DHEA, initiated at 2 wk of age, prevented the development of most diabetes symptoms and decreased the rate of weight gain in pups of all genotypes. In addition to therapeutic effects on both obese mutants, DHEA effected significant changes in an aging study using normal BL/6 female mice. Four weeks of DHEA treatment initiated at 2 yr of age improved glucose tolerance and at the same time reduced plasma insulin to a "younger" level. This suggests that DHEA may act in insulin-resistant mutant mice and in aging normal mice to increase the sensitivity to insulin.

Aging↗
PubMed1983

Cell-free synthesis and transport of precursors of mutant ornithine carbamoyltransferases into mitochondria.

Synthesis, mitochondrial transport and processing of ornithine carbamoyltransferase (EC 2.1.3.3) were studied in mutant mice strains (sparse-fur, spf, and sparse-fur with abnormal skin and hair, spf-ash) which exhibit a deficiency in this enzyme. Spf mice have an increased amount (about 150% of control) of the enzyme with abnormal kinetic properties, whereas spf-ash mice have a decreased amount (about 10% of control) of the enzyme with apparently normal kinetic properties. Precursors of the mutant enzymes were synthesized in a reticulocyte lysate cell-free system. The hepatic level of translatable mRNA coding for the enzyme and the rate of the enzyme synthesis in liver slices of spf mice were 58 and 60% of the controls, respectively. In the case of spf-ash mice the activity of translatable mRNA for the enzyme was 10% of the controls. These results indicate that the decreased amount of ornithine carbamoyltransferase protein in spf-ash mice is due mainly to a decreased level of translatable mRNA for the enzyme, whereas the increase in the enzyme amount in spf mice is presumably the result of a decreased rate of enzyme degradation. The subunit molecular weight of the spf enzyme precursor was practically the same as that of the normal enzyme precursor (Mr 40 000). Both precursors synthesized in vitro could be taken up and processed similarly to an apparently mature form (Mr 37 000). In the case of spf-ash enzyme, two discrete in vitro products were observed on sodium dodecyl sulfate polyacrylamide gel; one comigrated with the normal enzyme precursor and the other moved slightly slower. Both products appeared to be taken up and processed to the mature form of the enzyme.

Animals↗
PubMed2001

[The mouse model and human disease].

The mouse is an ideal model organism for studies of human disease, because mouse is physiologically very similar to human. Also, there is a large genetic reservoir of potential models of human diseases that has been generated. In addition, high-resolution genetic and physical linkage maps are now available and the sequence of mouse genome will be completed in the near future. Furthermore, the techniques necessary for the modification of mouse genome, such as transgenic and knockout techniques, and chromosome engineering methods have been established. These techniques enable us to introduce any mutations anywhere in the mouse genome. The methods for analyzing complex genetic diseases also have been developed. These advances facilitate the identification and cloning of mouse disease loci and the establishment of new models. It makes mouse the model organism of choice by academic and industrial researchers to study human diseases. In Part I of this review, we summarize the classical and modern approaches that provide the basis of establishing mouse model of human diseases. In the following parts, we will list more than 100 mouse models of human diseases. In most of these models, the mouse mutant phenotype closely resembles the human disease phenotype. These mouse models are valuable sources for the understanding of the human diseases and they can be used to develop strategies for prevention and treatment of the diseases.

Animals↗
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↗
PubMed2000

A late wave of melanoblast differentiation and rostrocaudal migration revealed in patch and rump-white embryos.

Melanocytes originate from a small number of precursors localized either side of the dorsal midline. The tyrosine kinase receptor Kit and its ligand Mgf (Steel Factor) are essential for melanoblast survival and proliferation during their migration from the neural crest. Inappropriate Kit expression in the dermatome and dermis of patch and rump-white mouse mutants apparently sequester Mgf, inhibiting melanoblast dispersal. Using a reporter transgene Dct-lacZ, extensive regions of the mutant trunks appear devoid of melanoblasts between E12.5 and E15.5, a much larger area than seen in mutant adults. Melanoblast recolonization of the underpopulated lumbar regions occurs very rapidly by E16.5 giving rise to patterns consistent with those observed in adults. The mutations permit observation of aspects of melanoblast development that are not seen, or are obscured, in normal embryos.

Animals↗
PubMed1995

IL-4 producing CD4+ TCR alpha beta int liver lymphocytes: influence of thymus, beta 2-microglobulin and NK1.1 expression.

The present report describes developmental, phenotypic and functional features of unconventional CD4+ TCR alpha beta lymphocytes. In C57BL/6 mice, the majority of liver lymphocytes expressing intermediate intensity of TCR alpha beta (TCR alpha beta int) are CD4+ NK1.1+ and express a highly restricted TCR V beta repertoire, dominated by V beta 8 with some contribution by V beta 7 and V beta 2. Although these cells express the CD4 co-receptor, they are present in H2-1 A beta (A beta)-/- gene disruption mutants but are markedly reduced in beta 2-microglobulin (beta 2m)-/- mutant mice and hence are beta 2m dependent. Thymocytes expressing the CD4+ NK1.1+ TCR alpha beta phenotype are also beta 2m contingent, suggesting that these two T lymphocyte populations are related. The CD4+ NK1.1+ TCR alpha beta lymphocytes in liver and thymus share several markers such as LFA-1+, CD44+, CD5+, LECAM-1- and IL-2R alpha-. The CD4+ NK1.1+ TCR alpha beta int liver lymphocytes were not detected in athymic nu/nu mice. We conclude that beta 2m expression is crucial for development of the CD4+ NK1.1+ TCR alpha beta int liver lymphocytes and that thymus plays a major role. CD4+ TCR alpha beta int liver lymphocytes were also identified in NK1.1- mouse strains, there lacking the NK1.1 marker. We assume that the NK1.1 molecule is a characteristic marker of the CD4+ TCR alpha beta int liver lymphocytes in NK1.1+ mouse strains, although its expression is not obligatory for their development. The liver lymphocytes from beta 2m+/-, but not from beta 2m-/-, mice are potent IL-4 producers in response to CD3 or TCR alpha beta engagement and the IL-4 production by liver lymphocytes was markedly reduced by treatment with anti-NK1.1 mAb. We conclude that the CD4+ NK1.1+ TCR alpha beta int liver lymphocytes are capable of producing IL-4 in response to TCR stimulation.

Animals↗
PubMed2000

Retention of PDGFR-beta function in mice in the absence of phosphatidylinositol 3'-kinase and phospholipase Cgamma signaling pathways.

Signal transduction by the platelet-derived growth-factor receptor beta (PDGFR-beta) tyrosine kinase is required for proper formation of vascular smooth muscle cells (VSMC). However, the importance of individual PDGFR-beta signal transduction pathways in vivo is not known. To investigate the role of two of the pathways believed to be critical for PDGF signal transduction, we have generated mice that bear a PDGFR-beta that can no longer activate PI3kinase or PLCgamma. Although these mutant mice have normal vasculature, we provide multiple lines of evidence in vivo and from cells derived from the mutant mice that suggest that the mutant PDGFR-beta operates at suboptimal levels. Our observations indicate that although loss of these pathways can lead to attenuated PDGF-dependent cellular function, certain PDGFR-beta-induced signal cascades are not essential for survival in mice.

Animals↗
PubMed2000

Retinal axon misrouting at the optic chiasm in mice with neural tube closure defects.

In a new mouse mutant, circletail (Crc), failure of neural tube closure (embryonic day [E] 8-9) is associated with errors in retinal axon projection at the optic chiasm (E12-18), such that many axons normally projecting contralaterally instead grow to ipsilateral targets. Although the architecture of the chiasmatic region is altered, neurons and glia containing putative cues for axon guidance are present. The aberrant ipsilateral-projecting cells originate from a nonrandom expansion of the wild-type uncrossed retinal region. These axon pathway defects are found in two other mutants with cephalic neural tube defects (NTD), loop-tail (Lp) and Pax3 (splotch; Sp(2H)). Crc is phenotypically similar to Lp, exhibiting an open neural tube from midbrain to tail (craniorachischisis), while splotch has spina bifida with or without a cranial NTD. The retinal axon abnormalities occur only in the presence of NTD and not in homozygous mutants lacking cranial NTD. Thus, failure of neural tube closure is associated with failure of many retinal axons to cross the ventral midline. This study therefore reveals an unexpected connection between closure of the neural tube at the dorsal midline and development of ventral axon tracts. genesis 27:32-47, 2000.

Animals↗
PubMed2006

Chemical identification of MHC-influenced volatile compounds in mouse urine. I: Quantitative Proportions of Major Chemosignals.

The genes of the major histocompatibility complex (MHC) are highly polymorphic loci that encode cell surface proteins, class I and II molecules. They present peptide antigens to T cells and thereby control immunological self/nonself recognition. Increasing evidence indicates that MHC genes also influence odor and mating preferences; however, it is unclear how. Here we report the results of chemical analyses of male mouse urinary odors collected from a variety of mouse strains, including MHC-congenics, recombinants, mutants, and transgenics (i.e., beta2 microglobulin "knockouts," which lack class I expression, and transporters associated with antigen processing (TAP) knock-outs). After the identification of volatile odor components by gas chromatography/mass spectrometry, the odor profiles of urine samples were analyzed quantitatively by using stir bar sorptive extraction and gas chromatography/atomic emission detection. Results showed that MHC genes influenced the amounts of testosterone-mediated pheromones, sulfur-containing compounds, and several carbonyl metabolites. This is the first report to quantitatively link known mouse pheromones to classical, antigen-binding MHC loci. Surprisingly, these compounds were not influenced by TAP genes, even though these loci are MHC-linked and play a role in peptide presentation. Whereas identification of MHC-determined odorants does not reveal their metabolic origin, some constituents were also present in blood serum, and their levels were not altered by antibiotics.

Animals↗
PubMed1999

Embryonic retinoic acid synthesis is essential for early mouse post-implantation development.

A number of studies have suggested that the active derivative of vitamin A, retinoic acid (RA), may be important for early development of mammalian embryos. Severe vitamin A deprivation in rodents results in maternal infertility, precluding a thorough investigation of the role of RA during embryogenesis. Here we show that production of RA by the retinaldehyde dehydrogenase-2 (Raldh2) enzyme is required for mouse embryo survival and early morphogenesis. Raldh2 is an NAD-dependent aldehyde dehydrogenase with high substrate specificity for retinaldehyde. Its pattern of expression during mouse development has suggested that it may be responsible for embryonic RA synthesis. We generated a targeted disruption of the mouse Raldh2 gene and found that Raldh2-/- embryos, which die at midgestation without undergoing axial rotation (body turning), exhibit shortening along the anterioposterior axis and do not form limb buds. Their heart consists of a single, medial, dilated cavity. Their frontonasal region is truncated and their otocysts are severely reduced. These defects result from a block in embryonic RA synthesis, as shown by the lack of activity of RA-responsive transgenes, the altered expression of an RA-target homeobox gene and the near full rescue of the mutant phenotype by maternal RA administration. Our data establish that RA synthesized by the post-implantation mammalian embryo is an essential developmental hormone whose lack leads to early embryo death.

Abnormalities, Multiple↗
PubMed1991

Rapid growth and spontaneous metastasis of human germinal tumors ectopically transplanted into scid (severe combined immunodeficiency) and scid-nudestreaker mice.

Xenograft acceptance, growth and spontaneous metastasis of ectopically transplanted human germinal tumors were compared among scid mice, athymic nude mice and F2 hybrids constructed from scid and nude mice, in relation to the impairments of T and B cell functions in these mice. In scid mice which are deficient in T and B cell functions, human yolk sac tumor (YST-2) that originated from the ovary grew to enormous sizes in 100% of the animals after both subcutaneous and intraperitoneal transplantation, while only half (59.1% and 51.9%) of the subcutaneous and none of the intraperitoneal transplants were accepted in usual athymic nude mice (BALB/c-nu/nu and CD1-nu/nu). The YST-2 grew rapidly in scid mice, developing 3 to 10 times larger tumors compared to nude-streaker (AKR/J-nustr/nustr) and usual nude mice, respectively. Furthermore, ectopically transplanted tumors spontaneously metastasized to distant organs (mostly to the lung) in scid mice (but less frequently in leaky scid mice), while metastases have never been found in nude mice. Although a xenograft of human classic (typical or pure) seminoma of the testis has never been established in nude mice, it grows slowly in one-third (36.4%) of scid mice and very rapidly in all of scid-nustr (scid/scid; nustr/nustr) double mutant mice. Spontaneous metastases of xenografted seminomas were also observed in distant organs (lymph node, lung, liver, spleen, and kidney). The metastastic distribution of the two human germinal tumors in scid and scid-nustr mice mimics that found in human. These results (xenograft acceptance, growth of transplanted tumors and degree of metastatic spread) were compatible with the level of T and B cell impairments indicated by FACS analysis, as well as mitogen responses, serum IgG and morphological features of the thymus.

Animals↗
PubMed2000

Bradykinin B2 null mice are prone to renal dysplasia: gene-environment interactions in kidney development.

Congenital abnormalities of the kidney and urinary tract are a common cause of end-stage renal disease in children. Host and environment factors are implicated in the pathogenesis of aberrant renal development. However, direct evidence linking gene-environment interactions with congenital renal disease is lacking. We report an animal model of renal dysgenesis that is dependent on a defined genetic defect and specific embryonic stressor. Specifically, mice that are deficient in the bradykinin type 2 receptor gene (B(2)) and salt loaded during embryogenesis acquire an aberrant kidney phenotype and die shortly after birth. In contrast, B(2) mutant mice maintained on normal sodium intake or salt-loaded wild-type mice do not develop kidney abnormalities. The kidney abnormality is evident histologically on embryonic day 16, shortly after the onset of metanephric B(2) gene expression, and consists of distorted renal architecture, foci of tubular dysgenesis, and cyst formation. The dysplastic tubules are of distal nephron origin [Dolichos biflorus agglutinin (DBA)- and aquaporin-2 (AQP2) positive, and angiotensinogen negative]. Neonatal antihypertensive therapy fails to ameliorate the renal abnormalities, arguing against the possibility that the nephropathy is a consequence of early hypertension. Moreover, the nephropathy is intrinsic to the embryo, because B(2) homozygous offspring from heterozygous parents exhibit the same renal phenotype as offspring from homozygous null parents. Further characterization of the renal phenotype revealed an important genetic background effect since the penetrance of the congenital nephropathy is increased substantially upon backcrossing of 129/BL6 B(2) mutants to a uniform C57BL/6J. We conclude that the type 2 bradykinin receptor is required for the maintenance of metanephric structure and epithelial integrity in the presence of fetal stress. This study provides a "proof-of-principle" that defined gene-environment interactions are a cause of congenital renal disease.

Angiotensinogen↗
PubMed1993

Pim-1 levels determine the size of early B lymphoid compartments in bone marrow.

The mouse proto-oncogene Pim-1, which encodes two cytoplasmic serine-threonine-specific protein kinases, is frequently activated by proviral insertion in murine leukemia virus-induced hematopoietic tumors. Transgenic mice overexpressing Pim-1 show a low incidence of spontaneous T cell lymphomas, whereas null mutant mice lack an obvious phenotype. We have analyzed the early B lymphoid compartment from both null mutant and E mu-Pim-1 transgenic mice. The level of Pim-1 expression appears to be a determining factor in the ability of these cells to respond to the growth factors interleukin 7 (IL-7) and SF (steel factor). The impaired response in null mutant mice could be rescued by introduction of a functional Pim-1 transgene. Moreover, overexpression of Pim-1 facilitates the derivation of primitive lymphoid cell lines that are dependent on combined stimulation with IL-7 and SF or insulin-like growth factor 1. These results for the first time identify the involvement of Pim-1 in a normal cellular function, as an important regulator of early B lymphopoiesis in mice.

Animals↗
PubMed1995

Stable production of mutant mice from double gene converted ES cells with puromycin and neomycin.

The antibiotic puromycin is an effective inhibitor of protein synthesis and puromycin N-acetyl transferase gene could be used as a dominant selection marker. We report the effective production of mutant mice from double gene-converted ES cells by selection with G418 and puromycin. We confirmed that (i) puromycin efficiently inhibited the growth of ES cells at a low-dose (0.1 microgram/ml) and for a short time (2 days), independent of G418 selection; (ii) when these selected ES cells were injected into eight-cell stage embryos, the cells produced chimeras with high levels of chimerism; (iii) these chimeric males were fertile and exclusively yielded ES cell-derived offspring; and (iv) each offspring contained both neomycin transferase and puromycin N-acetyl transferase genes.

Acetyltransferases↗
PubMed1999

Roles for PDGF-A and sonic hedgehog in development of mesenchymal components of the hair follicle.

Skin appendages, such as hair, develop as a result of complex reciprocal signaling between epithelial and mesenchymal cells. These interactions are not well understood at the molecular level. Platelet-derived growth factor-A (PDGF-A) is expressed in the developing epidermis and hair follicle epithelium, and its receptor PDGF-Ralpha is expressed in associated mesenchymal structures. Here we have characterized the skin and hair phenotypes of mice carrying a null mutation in the PDGF-A gene. Postnatal PDGF-A-/- mice developed thinner dermis, misshapen hair follicles, smaller dermal papillae, abnormal dermal sheaths and thinner hair, compared with wild-type siblings. BrdU labeling showed reduced cell proliferation in the dermis and in the dermal sheaths of PDGF-A-/- skin. PDGF-A-/- skin transplantation to nude mice led to abnormal hair formation, reproducing some of the features of the skin phenotype of PDGF-A-/- mice. Taken together, expression patterns and mutant phenotypes suggest that epidermal PDGF-A has a role in stimulating the proliferation of dermal mesenchymal cells that may contribute to the formation of dermal papillae, mesenchymal sheaths and dermal fibroblasts. Finally, we show that sonic hedgehog (shh)-/- mouse embryos have disrupted formation of dermal papillae. Such embryos fail to form pre-papilla aggregates of postmitotic PDGF-Ralpha-positive cells, suggesting that shh has a critical role in the assembly of the dermal papilla.

Actins↗
PubMed1997

Neuronal nitric oxide synthase mutant mice show smaller infarcts and attenuated apparent diffusion coefficient changes in the peri-infarct zone during focal cerebral ischemia.

Diffusion-weighted MRI at 2 T was used to monitor and assess tissue damage after permanent middle cerebral artery occlusion (MCAO) in wild-type (WT) and mice deficient in nitric oxide synthase gene expression (nNOS-). The ischemic lesion was evaluated 3 h after occlusion and subdivided into the lesion core and peri-infarct zone based on the magnitude of the apparent diffusion coefficient (ADC) change. Infarct volume, measured by using histochemical staining 24 h after MCA occlusion, correlated best with MRI infarct volume as assessed by an ADC threshold of 25% decrease from baseline at 3 h. For ADC thresholds of greater than 25% decrease, lesion size was not significantly different in nNOS- and WT mice. However, brain tissue showing ADC decreases of 10-25% was significantly smaller in the ipsilateral hemisphere of mutants (27 +/- 2% and 21 +/- 2% in WT and nNOS-, respectively; P < 0.05). These findings occurred independently of infarct volume and are consistent with a smaller peri-infarct zone in nNOS- mice. We postulate that the smaller peri-infarct zone is a reflection of less severe metabolic disturbance after ischemia in nNOS- mice, possibly related to diminished production of nitric oxide (NO) or a related product. We conclude that magnetic resonance techniques previously used to assess ischemic damage in larger animals can be extended to the mouse, raising the possibility that the molecular mechanisms leading to ischemic damage can be examined by using genetically engineered mice.

Animals↗
PubMed1993

Epidermal dendritic cell populations in the flaky skin mutant mouse.

Flaky skin (gene symbol: fsn) is an autosomal recessive mouse mutation that causes pathologic changes in the skin yielding a papulosquamous disease resembling human psoriasis. Preliminary studies of epidermal sheets from foot pads of fsn/fsn mice stained for Ia+ Langerhans cells (LC) or Thy-1+ dendritic epidermal cells (Thy-1+ DEC) indicated a rise in LC numbers at the time of weaning, when the skin lesion becomes clinically evident. To further investigate this observation, epidermal sheets were obtained from the ear, dorsal skin, and foot pads from replicates of 6 female mice (both mutants and normal littermates) on weekly intervals from birth to 8 weeks of age. Dorsal skin epidermal thickness was quantitated by computer assisted image analysis and found to be significantly thickened from one week onward in the mutant mice. Using immunofluorescence microscopy, epidermal dendritic cell numbers were determined following staining with antibodies for the following markers: Ia, NLDC-145, and S-100 (for LC) or Thy 1.2 and asialo-GM1 (for Thy-1+ DEC). Use of all 5 markers to evaluate skin from 3 different locations yielded a subtle but significant increase in LC and Thy-1+ DEC in flaky skin mice. Of the three sites evaluated, the dorsal skin and ear epidermal sheets were most informative, which corresponded to the degree of pathological involvement. Mice doubly homozygous for fsn and for the severe combined immunodeficiency (scid) mutation developed the psoriasiform dermatitis. Bone marrow grafts from fsn/fsn homozygotes to homozygous scid/scid mice reproduce the skin lesion. These studies suggest that the psoriasiform dermatitis in the flaky skin mouse mutation is associated with abnormalities at the level of hematopoietic progenitor cells.

Aging↗