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Disease of the kidney developed in breeding stock of Gunn rats. The renal lesion is the result of a new mutation. The genetic defect is inherited as an autosomal dominant trait and is apparently lethal in the homozygous condition. The abnormality manifests itself as a congenital hydronephrosis with related cystic changes in the kidney.
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Long-Evans Cinnamon (LEC) rat is an inbred strain of mutant rat which has been proposed to be an animal model for human Wilson's disease. In the present study, 28 genetic marker proteins were analyzed by electrophoresis in sublines of LEC inbred strain held separately by four facilities. As expected, the 27 markers were homozygous and identical in all of examined animals. We further found a novel variant of esterase-2 (ES-2) showing an intermediate mobility between profiles of ES-2A and ES-2C types.
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A new mutant derived from the Zucker rat strain called stargazer (homozygous stg/stg) displays abnormal behavior that is characterized by pronounced arching of the neck ("stargazing"), rapid circling, and conspicuous hyperactivity. Results of serologic assays performed by two independent diagnostic laboratories have indicated that the abnormal behavior in the stargazer is not the result of a viral or bacterial infection. In this report, different groups of stargazer rats and their normal-behaving littermates (heterozygous stg/+) were assessed with regard to spontaneous behaviors, heart rate, blood pressure, and plasma biochemical profiles. Besides frequent stargazing, the predominant behavioral feature of the stargazers was extreme hyperactivity; they had sevenfold greater activity than the normal littermates (P < 0.05), expressed in the form of rapid ambulation and tail-chasing. The stargazers had significantly greater daily calorie and water consumption, despite being significantly smaller in body weight than the littermates (P < 0.05 for all). However, urine output was not different between the two groups. Heart rate and blood pressure also were not different. Stargazers had significantly lower total triglycerides concentration and lower aminotransferase activity than littermates (P < 0.05 for both), a finding probably related to their smaller body size. It is concluded that stargazer rats are extremely hyperactive but normotensive; heterozygous littermates are behaviorally normal, despite being carriers of the stg gene; and routine diagnostic blood testing revealed no important differences between the stargazers and their unaffected littermates.
A jaundiced rat strain was derived from a cross between Gunn and Wistar-Imamichi rats, and inbreeding was continued by forced heterozygosis with jaundice locus. These Gunn rats have black pigment on heads and a black stripe on their backs similar to Long-Evans rats. Wistar rats with low activity in androsterone (AD) glucuronidation were selected and inbred (LA Wistar rats). The levels of hepatic uridine diphosphate-glucuronosyltransferase (GT) and sulfotransferase (ST) activities as well as cytochrome P-450 contents were compared in these mutant strains. Gunn rats were devoid of bilirubin (BL) GT activity but had high AD GT activity. LA Wistar rats had very low AD GT activity but showed high BL GT activity. Native and Triton X-100-stimulated GT activities toward 2-aminophenol and 4-nitrophenol (NP) were much lower in Gunn rats than in LA Wistar rats. When N-nitrosodiethylamine was added to the incubation media, these GT activities were stimulated equally to high levels in both mutants. N-Nitrodiethylamine provided a similar stimulatory effect on NP GT activity. There were no significant differences in ST activities toward cortisol, AD and NP and cytochrome P-450 contents in the two mutant strains. These results indicate that Gunn and LA Wistar rats have a different deficiency in GT isoenzymes.
There are advantages and disadvantages to all animal models for aging research. Investigators need to understand these issues as well as the nature of each relevant model, in order to choose the best model for their research. There is no "best" or "worst" model for aging research. Five genetically defined rodent models of potential utility in aging research are: 1. Inbred strains and F1 Hybrid mice and rats; 2. Single gene mutations and other single locus effects; 3. Congenic lines; 4. Recombinant Inbred (RI) strains; 5. Genetically selected strains and stocks. Animals of each of these types are available for research, but only inbred and F1 hybrid mice and rats are commercially available as aged animals. A general understanding of the need for careful genetic definition and for the best available barrier-breeding facilities has improved the quality of aging research significantly in the last two decades.
The dermal histology and the regional draining superficial lymph node of a new mutant strain of hairless rats (ISh) were investigated. The homozygote ISh rat was characterized as having naked and wrinkled skin. The comedo-like cysts in the skin resembled human acne and vulgaris. Histopathologically, many Langerhans' cells positive for anti-protein kinase C type II antibody (PKC-II) were recognized in the epidermis. The superficial lymph nodes were significantly larger than those of the heterozygote. The paracortex of these lymph nodes was expanded and the number of Langerhans' cells mainly increased in these areas. These lymph node lesions were similar to those of human dermatopathic lymphadenopathy. The ISh rats should be a very useful animal model for studying dermatopathic lymphadenopathy in humans. Furthermore, they may be a valuable animal model for investigating the mechanisms of not only maturation, movement and migration of Langerhans' cells, but also of their function for antigen presentation.
We have previously reported that insulin binding is decreased in the olfactory bulb of both heterozygous (Fa/fa) and obese (fa/fa) Zucker rats. In the present study, we measured insulin binding in membranes prepared from the olfactory bulb, cerebral cortex, and hypothalamus of control (Fa/Fa) Wistar Kyoto rats; "fatty" (fa/fa) Wistar Kyoto rats; and phenotypically lean (Fa/?) Wistar Kyoto rats. Insulin binding was decreased in all brain regions, as well as the liver of the obese Wistar Kyoto fa/fa rats. Additionally, insulin binding was decreased in the liver and brain membranes from the Fa/? Wistar Kyoto rats. As most of the Fa/? rats were probably carriers of one 'fa' gene, but the population was only slightly hyperinsulinemic, we conclude that--as in the Zucker rat--it is the presence and expression of the 'fa' gene rather than downregulation which results in the decreased insulin binding. Thus, regulation of the brain insulin receptor appears to be independent of plasma or cerebrospinal fluid insulin levels.
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A mutant strain of rat, LEC, shows a novel arrest of T-cell maturation from CD4+8+ to CD4+8-, but not to CD4-8+ cells in the thymus. The responsible mutant locus is designated the thid, which was acted upon in a recessive manner of inheritance. We found that LEC rat thymocytes failed to respond to interleukin (IL)-1, IL-6 and IL-7 in the presence of the mitogenic lectins, Allo A or concanavalin A (Con A). The unresponsiveness appeared to be due to unresponsiveness to the lectin stimulation rather than because of cytokine stimulation. Normal rat CD4-8+/- (consisting of CD4-8+ and CD4-8- thymocytes), CD4+/-8- (consisting of CD4+8- and CD4-8- thymocytes), and CD4-8- thymocyte subsets normally responded to mitogenic stimulation, while CD4+8+ thymocytes did not. In contrast, all LEC rat CD4-8+/-, CD4+/-8-, CD4-8- and CD4-8+ thymocytes did not respond to the mitogenic stimulation, suggesting that the unresponsiveness of the CD4-8+/- thymocytes seems to be responsible for the unresponsiveness of whole thymocytes in LEC rats. LEC rat CD4-8+/- thymocytes normally expressed Con A receptor (R), lymphocyte function-associated antigen-1 (LFA-1), and CD45, which are thought to be important molecules for lectin stimulation. When backcross rats from (F344xLEC)F1xLEC were examined, the phenotype for the thid mutation correlated with the [3H]thymidine deoxyribose (TdR) incorporation level in response to Con A stimulation; thymocytes from backcross rats showing +/thid phenotype responded to Con A stimulation normally, whereas thymocytes from backcross rats showing thid/thid phenotype showed significantly lower responsiveness compared with +/thid rats. However, in WKAH.C-thid congenic rat thymocytes that carry the thid mutation, the responsiveness to mitogenic stimulation was comparable to that of normal rat thymocytes. These results suggest that a defect in responsiveness to mitogenic stimulation in LEC rat thymocytes is controlled by multiple genetic loci and the thid locus is one of the important loci for the development of this abnormal phenotype.
The ability of natural killer (NK) cells to eliminate normal allogeneic hemic cells is well established in several species including mice, rats, and humans. The controlling elements for NK susceptibility in these species map to the major histocompatibility complex (MHC), but in contrast to findings in mice and humans, the mode of inheritance is not always recessive in rats. This finding is not easily explained by the missing self and hemopoietic histocompatibility (Hh) models for NK recognition, and has led to the idea that certain alloantigens may trigger NK cell reactivity. In our in vitro system for assessing rat NK alloreactivity, we have employed target and inhibitor cells from a large panel of MHC congenic, intra-MHC recombinant and MHC mutant rat strains, as well as appropriate F1 hybrids between them, and we show the following: (a) The nonclassical class I (RT1.C) region was most important in determining the susceptibility of target cells to alloreactive NK cells in vitro. Lymphocyte susceptibility to lysis in vivo also mapped to the C region, which supports the concept that the in vivo and in vitro alloreactivity assays reflect the same recognition process. (b) Four different RT1-controlled NK allospecificities (represented by the u, l, a, and n haplotypes) could be discerned when we used polyclonal NK cells from the PVG (RT1c) strain as effector cells. Three of the target specificities recognized were controlled mainly by the RT1.C region. (c) The expression of RT1.C region-controlled parental strain NK allodeterminants could be demonstrated in F1 hybrids heterozygous for the C region alone and were therefore inherited nonrecessively. (d) Loss of an RT1.C region-controlled NK allospecificity could be shown with the MHC mutant LEW.1LM1 rat strain characterized by a genomic deletion of about 100 kb of the C region. Taken together, these observations have demonstrated a major importance of the nonclassical class I region, i.e., RT1.C, in controlling rat NK allorecognition, and have thereby assigned a hitherto undescribed immunological property to this region. Furthermore, some of the present data are consistent with the existence of polymorphic NK-triggering alloantigens that are coded for by the RT1.C region.
Recent experimental evidence suggests that insulin-like growth factor-I (IGF-I) may be involved in compensatory renal growth (CRG). This study was designed to determine the relative contribution of IGF-I and growth hormone (GH) to the CRG that takes place in rats following uninephrectomy (UNx). We also studied the respective role of GH and IGF-I in the stimulation of CRG induced by a high protein diet (HPD). CRG was studied 7 days after UNx in Wistar rats and in a new mutant strain of dwarf rats, selectively deficient in GH. Prior to UNx, rats of both strains were pre-fed (14 days) either a medium-protein diet (MPD, casein 18%) or a HPD (54%). On MPD, CRG was comparable in Wistar (17.6 +/- 3.1%, M +/- SD) and dwarf (14.4 +/- 4.8%) rats. The HPD enhanced CRG in the Wistars (27 +/- 3.9%, P less than 0.005) but not in the dwarfs (14.9 +/- 2%). CRG in both experimental groups involved renal hypertrophy and hyperplasia. Control (baseline) serum, liver and kidney IGF-I were significantly less in dwarf rats. However, following UNx, on a MPD, kidney IGF-I increased significantly in both Wistar and dwarf rats: Wistar, pre-UNx, 310 +/- 46 ng/g tissue; post-UNx, 405 +/- 54 ng/g, P less than 0.005; dwarfs, pre-UNx, 205 +/- 35 ng/g; post-UNx 426 +/- 90 ng/g, P less than 0.001. On a HPD a further significant increase in renal IGF-I was only observed in Wistar rats (505 +/- 46 ng/g). No change in serum or liver IGF-I was observed after UNx in either strain.(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND/AIMS: Several studies have suggested that mast cells participate in the development of liver fibrosis in rodent models. In this study mast cell-deficient mutant Ws/Ws rats and W/Wv mice were used to examine whether mast cells are involved in the development of liver fibrosis. METHODS: Liver fibrosis was induced in rats by bile duct resection (BDR), and by intraperitoneal injections of carbon tetrachloride (CCl4) or porcine serum, and in mice by intragastric administrations of CCl4, and BDR. The degree of fibrosis was evaluated by measuring the hydroxyproline content (microg/mg tissue) of the liver as an index of the collagen content. The density of mast cells (number/cm2 liver section) was determined by counting mast cells in liver sections stained with alcian blue. RESULTS: In the liver of control non-mutant (+/+) rats, mast cells were found principally in portal areas, and their average density was 200-300/cm2 liver section. BDR, and treatments with CCl4 and porcine serum increased the density of mast cells in the liver of +/+ rats several-fold, and induced liver fibrosis, increasing the liver hydroxyproline content markedly. BDR, and treatments with CCl4 and porcine serum also induced liver fibrosis in Ws/Ws rats, increasing the liver hydroxyproline content to a similar or higher level than that in +/+ rats. However, the average densities of mast cells in the liver of Ws/Ws rats after BDR and treatment with CCl4 and porcine serum were at most 10.2/cm2 liver section. The density of mast cells in the liver of control +/+ mice was extremely low (average, less than 2), and neither BDR nor treatment with CCl4 caused any significant increase in their density, whereas these treatments induced liver fibrosis and markedly increased the liver hydroxyproline content. Furthermore, treatment with CCl4 induced fibrosis in the liver of W/Wv mice similarly to that in +/+ mice, but the density of mast cells in the liver of W/Wv mice was very low (average, less than 1), and was not increased by treatment with CCl4. CONCLUSIONS: The present results indicate that mast cells play no role in the development of liver fibrosis in rats and mice.
In the normal (Wistar) rat vasopressin encoding mRNA first appears at embryonic day 15 as demonstrated by in situ hybridization of hypothalamic sections. In mutant (Brattleboro) rats, which possess a defective vasopressin gene with a single nucleotide deletion, the corresponding transcript is not detectable before fetal day 18. In both rat strains however expression of the structurally related oxytocin gene begins at fetal day 19. Whereas normal and mutant vasopressin encoding mRNAs are identical in size up to at least three weeks after birth, the corresponding transcripts from adult Brattleboro but not from normal rats are markedly larger. This increase in size is due to a longer stretch of poly(A) sequence as demonstrated by treatment of the respective mRNAs with RNase H and oligo(dT). Thus the mutant vasopressin gene transcript is subject to a cellular-specific differential polyadenylation process during development.
It is clear that a variety of gene defects can result in absence seizures. In addition, the problem is complicated by observation that the behavioral and EEG phenotype in some of the models is highly dependent on pedigree. Despite these difficulties, advances in molecular-genetic techniques coupled with electrophysiological studies are likely to be highly revealing. While the relationship between the rat and mice models and the human condition thus far remains tenuous, insights from the animal models have already been very helpful in choosing antiepileptic drugs and providing insights into the pathophysiology of the seizures.
The rat cytomegalovirus (RCMV) R78 gene belongs to an uncharacterized class of viral G protein-coupled receptor (GCR) genes. The predicted amino acid sequence of the R78 open reading frame (ORF) shows 25 and 20% similarity with the gene products of murine cytomegalovirus M78 and human cytomegalovirus UL78, respectively. The R78 gene is transcribed throughout the early and late phases of infection in rat embryo fibroblasts (REF) in vitro. Transcription of R78 was found to result in three different mRNAs: (i) a 1.8-kb mRNA containing the R78 sequence, (ii) a 3.7-kb mRNA containing both R77 and R78 sequences, and (iii) a 5.7-kb mRNA containing at least ORF R77 and ORF R78 sequences. To investigate the function of the R78 gene, we generated two different recombinant virus strains: an RCMV R78 null mutant (RCMVDeltaR78a) and an RCMV mutant encoding a GCR from which the putative intracellular C terminus has been deleted (RCMVDeltaR78c). These recombinant viruses replicated with a 10- to 100-fold-lower efficiency than wild-type (wt) virus in vitro. Interestingly, unlike wt virus-infected REF, REF infected with the recombinants develop a syncytium-like appearance. A striking difference between wt and recombinant viruses was also seen in vivo: a considerably higher survival was seen among recombinant virus-infected rats than among RCMV-infected rats. We conclude that the RCMV R78 gene encodes a novel GCR-like polypeptide that plays an important role in both RCMV replication in vitro and the pathogenesis of viral infection in vivo.