Two lines of E alpha d-expressing NOD mice were established by continuously backcrossing [E alpha d B6 transgenic mice x NOD] F1 to parental NOD or directly microinjecting the E alpha d gene into fertilized NOD eggs. Similarly, A beta k-expressing transgenic NOD mice were produced. Subsequent histological examination of pancreatic tissues revealed that autoimmune insulitis was prevented in E alpha d backcross and transgenic mice but not in A beta k transgenic mice.
To analyze the regulation of transthyretin gene expression we have produced transgenic mice by microinjecting cloned human transthyretin genes into fertilized eggs of C57BL/6 mice. The 7.6-kilobase (kb) human transthyretin gene containing about 500 base pairs (bp) in the upstream region was used for microinjection. Seven out of nine transgenic mice had detectable amounts of human transthyretin in serum when analyzed by enzyme-linked immunosorbent assay. Transthyretin mRNA was detected in liver and yolk sac but not in other tissues including brain. The amount of mRNA was variable among transgenic mice and was about one-tenth of mouse endogenous transthyretin mRNA. Human and mouse transthyretin mRNAs were detected in liver of fetus and yolk sac at 13 days of gestation and unlike yolk sac the level of mRNA in liver increased gradually during development and reached the maximum at around 17 days of gestation. Human transthyretin was associated with mouse transthyretin to form tetramers as judged from the dilution curve of enzyme-linked immunosorbent assay and the spur formation in Ouchterlony assay.
The involvement of dysregulated c-myc expression has been well established in certain virus-or chemical-induced and naturally developing tumors (1-5). Most of murine plasmacytomas and human Burkitt's lymphomas have been shown to carry a chromosomal translocation involving c-myc and Ig genes (2-5). In such tumor cells, only the c-myc transcripts from the translocated allele are constitutively expressed, while the normal allele is completely suppressed, suggesting that the translocation affects the expression of the c-myc gene of the normal allele as well as that of the translocated one (6, 7). Recently it has been shown that Ig heavy chain enhancer (Ew) t-driven c-myc can induce immature B cell tumors in the transgenic mice (8), which is a direct demonstration of the involvement of the translocated c-myc gene in B lymphomagenesis . Moreover, tumors developed in such transgenic mice have been demonstrated to be monoclonal or oligoclonal, suggesting that the malignant transformation requires secondary events following an abnormal expression of c-myc gene. It is likely that such events might be determined or influenced by factors intrinsic to certain cells, or by environmental and genetic factors. Thus, the transgenic mice carrying activated oncogenes such as c-myc can also be a useful system to study such factors influencing tumorigenesis.To study the genetic or environmental factors that affect the myc-induced lymphomagenesis, we introduced the translocated human c-myc gene into two inbred strains ofmice, C57BL/6 and C3H/HeJ, which have different genetic backgrounds. We have observed the preferential development ofT lymphomas in C3H/HeJ transgenic mice, whereas B6 transgenic mice mostly developed B lymphomas. Furthermore, the bone marrow transfer experiments using prelymphomatous transgenic mice suggest that environmental factors might influence the development ofT lymphoma in C3H/HeJ mouse.
We have created a transgenic mouse which showed an autosomal dominant mutation of facial development. This facial malformation was characterized by a short snout and a twisted upper jaw. All offspring showing the dysmorphic phenotype carried the injected gene. In order to analyze the primary cause of this mutation, newborn mice and embryos were examined. The outcome was that the malformation of nasal and premaxillary bone was not the primary defect but was a secondary event. The primary cause of this dysmorphism was a developmental defect in the first branchial arch. Genomic DNA fragments flanking the insertion site of this mutant mouse were cloned. Using these fragments, we have assigned the integration site to chromosome 13. The gene responsible for a previously reported mutant mouse, one which also has a short snout, is also reported to be on chromosome 13. In the fragments flanking the insertion site of the transgenic mouse, at least one fragment was highly conserved in mammals. These results indicate that this malformation is due to the insertional disruption of a host gene. However, the possibility that this mutation is caused by an inappropriate expression of the injected gene still remains to be investigated.
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