LCR-Fl is a mammalian bZIP transcription factor containing a basic amino acid domain highly homologous to a domain in the Drosophila Cap 'N' Collar and Caenorbabditis elegans SKN-1 proteins. LCR-Fl binds to API-like sequences in the human p-globin locus control region and activates high-level expression of p-globin genes. To assess the role of LCR-Fl in mammalian development, the mouse Lcrfl gene was deleted in embryonic stem (ES) cells, and mice derived from these cells were mated to produce Lcrfl null animals. Homozygous mutant embryos progressed normally to the late egg cylinder stage at -6.5 days post coitus (dpc), but development was arrested before 7.5 dpc. Lcrfl mutant embryos failed to form a primitive streak and lacked detectable mesoderm. These results demonstrate that LCR-Fl is essential for gastrulation in the mouse and suggest that this transcription factor controls expression of genes critical for the earliest events in mesoderm formation. Interestingly, Lcrfl null ES cells injected into wild-type blastocysts contributed to all mesodermally derived tissues examined, including erythroid cells producing hemoglobin. These results demonstrate that the Lcrfl mutation is not cell autonomous and suggest that LCR-Fl regulates expression of signaling molecules essential for gastrulation. The synthesis of normal hemoglobin levels in erythroid cells of chimeras derived from Lcrfl null cells suggests that LCR-Fl is not essential for globin gene expression. LCR-Fl and the related bZIP transcription factors NF-E2 p45 and NRF2 must compensate for each other in globin gene regulation.
j80-Thalassemia is an inherited disorder characterized by the absence of 1-globin polypeptides derived from the affected allele. The molecular basis for this deficiency is a mutation of the adult 18-globin structural gene or cis regulatory elements that control 13-globin gene expression. A mouse model of this disease would enable the testing of therapeutic regimens designed to correct the defect. Here we report a 16-kb deletion that includes both adult 13-like globin genes, 13maJ and pmin, in mouse embryonic stem cells. Heterozygous animals derived from the targeted cells are severely anemic with dramatically reduced hemoglobin levels, abnormal red cell morphology, splenomegaly, and markedly increased reticulocyte counts. Homozygous animals die in utero; however, heterozygous mice are fertile and transmit the deleted allele to progeny. The anemic phenotype is completely rescued in progeny derived from mating PO-thalassemic animals with transgenic mice expressing high levels of human hemoglobin A. The PO-thalassemic mice can be used to test genetic therapies for j3O-thalassemia and can be bred with transgenic mice expressing high levels of human hemoglobin HbS to produce an improved mouse model of sickle cell disease.Homozygous 130-thalassemia in humans is characterized by severe anemia that begins during the first month of life (1). As
The value of the zebrafish (Danio rerio) as a model organism continues to expand. In developing the model, current feeding practice in zebrafish laboratories includes the use of commercially available diets. In this study, we compared outcomes in growth, body composition, and reproduction among zebrafish fed five highly utilized commercial diets and one formulated chemically defined reference diet. Wild-type zebrafish larvae were raised on live feed until 21 days postfertilization and then fed diets for 16 weeks. All fish received a daily ration of >5% of body weight (adjusted biweekly). Growth varied among diets throughout the feeding trial, and at study termination (week 16), significant differences among diets were observed for terminal weight gain, body condition index, body fat deposition, and reproductive outcomes. In addition, the proportion of viable embryos produced from females fed the formulated reference diet was high relative to the commercial diets. These data suggest that metabolic profiles, most likely reflecting nutrient/energy availability, utilization, and allocation, vary relative to diet in zebrafish. Undefined differences in metabolic profiles could result in erroneous predictions of health outcomes and make comparisons among laboratories more challenging. We recommend that dietary standards should be defined for zebrafish to support their common utility in biomedical research.
The exchange of fish for research may expose an aquatic laboratory to pathogen contamination as incoming fish can introduce bacteria, fungi, parasites, and viruses capable of affecting both experimental results and fish and personnel health and welfare. To develop risk mitigation strategies, FELASA and AALAS established a joint working group to recommend good practices for health monitoring of laboratory fish. The recommendations address all fish species used for research, with a particular focus on zebrafish (Danio rerio). First, the background of the working group and key definitions are provided. Next, fish diseases of high impact are described. Third, recommendations are made for health monitoring of laboratory fishes. The recommendations emphasize the importance of daily observation of the fish and strategies to determine fish colony health status. Finally, report templates are proposed for historical screening data and aquatic facility description to facilitate biohazard risk assessment when exchanging fish.
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