These findings identify the presence of the rd8 mutation in the C57BL/6N mouse substrain used widely to produce transgenic and knockout mice. The results have grave implications for the vision research community who develop mouse lines to study eye disease, as presence of rd8 can produce significant disease phenotypes unrelated to the gene or genes of interest. It is suggested that researchers screen for rd8 if their mouse lines were generated on the C57BL/6N background, bear resemblance to the rd8 phenotype, or are of indeterminate origin.
The transcription factor Meis1 is expressed preferentially in hematopoietic stem cells (HSCs) and overexpressed in certain leukemias. However, the functions of Meis1 in hematopoiesis remain largely unknown. In the present study, we found that Meis1 is required for the maintenance of hematopoiesis under stress and over the long term, whereas steadystate hematopoiesis was sustained in the absence of Meis1 in inducible knock-out mice. BM cells of Meis1-deficient mice showed reduced colony formation and contained significantly fewer numbers of long-term HSCs, which exhibited loss of quiescence. Further, we found that Meis1 deletion led to the accumulation of reactive oxygen species in HSCs and decreased expression of genes implicated in hypoxia response. Finally, reac- IntroductionThe transcription factor Meis1 belongs to the 3-amino acid loop extension (TALE) family of homeodomain proteins, which also includes Pbx1. Meis1 was originally discovered as a target of activation by retroviral integration in the leukemic mouse strain BXH-2. In these mice, Meis1 was always found coactivated with Hoxa7 or Hoxa9. 1 Experimental overexpression of Meis1 and Hoxa9 in hematopoietic cells leads to an aggressive leukemia in mice. 2 In normal hematopoiesis, Meis1 expression among the various cell compartments is correlated with the degree of selfrenewal, with the levels being highest in hematopoietic stem cells (HSCs) and declining with differentiation. 3,4 These results, combined with those from studies in leukemia, suggest a role for Meis1 in HSC self-renewal. However, the functions of Meis1 in established hematopoiesis remain unknown. Meis1 Ϫ/Ϫ mice die by embryonic day 14.5 and the embryos display extensive hemorrhaging, particularly in the CNS. In addition, fetal liver cells obtained from Meis1 Ϫ/Ϫ embryos show reduced myeloid colony formation in vitro and perform poorly in competitive transplantation assays in vivo. 5,6 These results show that Meis1 is critical in the development of hematopoiesis. Further, Meis1 Ϫ/Ϫ embryos display defects in capillary formation, suggesting additional roles for Meis1 in mechanisms that regulate the process of angiogenesis, at least during development.Previous studies showed that Meis1 and Pbx1 can form heterodimeric and heterotrimeric complexes with HOX proteins, augmenting the binding and activation of target genes by HOX proteins such as HOXA9. 7,8 Deletion of Pbx1 in the hematopoietic system led to loss of quiescence in HSCs, resulting in hematopoietic failure. 9 Given that both Pbx1 and Meis1 are expressed in HSCs, we hypothesized that Meis1 might also be required for the maintenance of the self-renewing HSCs. In the present study, we investigated the role of Meis1 in established hematopoiesis using inducible knock-out mice. We found that Meis1 is required for the maintenance of HSCs by preserving quiescence in these mice. Maintenance of quiescence is critical for preserving self-renewal of long-term stem cells, and various signaling pathways have been shown to modulate quiescence in HSC...
Purpose Classical pharmacology allows the use and development of conventional phytomedicine faster and more economically than conventional drugs. This approach should be tested for their efficacy in terms of complementarity and disease control. The purpose of this study was to determine the molecular mechanisms by which nimbolide, a triterpenoid found in the well-known medicinal plant Azadirachta indica controls glioblastoma (GBM) growth. Experimental Design Using in vitro signaling, anchorage-independent growth, kinase assays, and xenograft models, we investigated the mechanisms of its growth inhibition in glioblastoma. Results We show that nimbolide or an ethanol soluble fraction of A. indica leaves (Azt) that contains nimbolide as the principal cytotoxic agent is highly cytotoxic against GBM in vitro and in vivo. Azt caused cell cycle arrest, most prominently at the G1-S stage in GBM cells expressing EGFRvIII, an oncogene present in about 20-25% of GBMs. Azt/nimbolide directly inhibited CDK4/CDK6 kinase activity leading to hypophosphorylation of the retinoblastoma (RB) protein, cell cycle arrest at G1-S and cell death. Independent of RB hypophosphorylation, Azt also significantly reduced proliferative and survival advantage of GBM cells in vitro and in tumor xenografts by downregulating Bcl2 and blocking growth factor induced phosphorylation of Akt, Erk1/2 and STAT3. These effects were specific since Azt did not affect mTOR or other cell cycle regulators. In vivo, Azt completely prevented initiation and inhibited progression of GBM growth. Conclusions Our preclinical findings demonstrate Nimbolide as a potent anti-glioma agent that blocks cell cycle and inhibits glioma growth in vitro and in vivo.
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