Notch1 perturbation of lymphoid b and myeloid development is associated with upregulation of hes1/ hes5 and secreted factors
Notch is known to play a critical role in cell fate decision in the development of multiple tissues. To explore Notch 1 signaling in hematopoiesis, we generated a series of transplanted mice overexpressing activated Notchl (Notchl 1C) or Hes genes, which are downstream effectors of Notch 1. Chimeric mice obtained by transplantation of bone marrow (BM) progenitors retrovirally transduced with Notchl 1C developed T cell leukemia of donor origin, while both the host and donor hematopoietic compartments totally lacked B cells, suggesting that the transduced cells altered the maturation of the non-transduced fraction. In mice transplanted with Hesl and Hes5 we found a suppression of B cell development only among the donor-transduced cells. Northern blotting analysis demonstrated that Hesl and Hes5 were upregulated in the BM of Notchl 1C transplanted mice. In addition, an E box reporter assay showed that Hesl, Hes5 or Notchl 1C overexpression inhibited the transactivating properties of E2A. These results indicate that the perturbation of B cell development among the Notchl IC-transduced BM cells could be mediated in part by the up-regulation of Hesl/Hes5 and the ability of these proteins to repress the transcriptional activity of E2A. To explore the effect of Notch 1 signaling on myeloid development, we studied the colony forming potential of BM cells from Notchl 1C mice, and found that the transduced cells remained immature in the presence of myeloid growth factors, while the non-transduced cells did not grow, suggesting they were already matured. The perturbation of B cell and myeloid development among the non-transduced cells of the Notchl 1C transplanted mice prompted us to explore the existence of a cell-nonautonomous mechanism mediated by Notchl 1C. We found that the suppression of B cells among the non-transduced compartment was proportional to the percentage of cells transduced by Notchl 1C at the time of transplantation. Further, we demonstrated that the culture media of Notchl 1C BM cells contained activity which could inhibil B cell development and promote myeloid maturation of progenitors in a dose dependent manner. These findings show that the alteration of B lymphoid and myeloid development by activated Notchl combines intrinsic perturbations of the genetically modified cells, possibly mediated by Hesl/HesS upregulation, and cell-nonautonomous modifications of the non-transduced cells mediated by soluble factors.
Kawamata, S; Du, C; O'Farrell, AM; Murray, L; Lavau, C
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