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Pbx1 regulates self-renewal of long-term hematopoietic stem cells by maintaining their quiescence.

Self-renewal is a defining characteristic of stem cells; however, the molecular pathways underlying its regulation are poorly understood. Here, we demonstrate that conditional inactivation of the Pbx1 proto-oncogene in the hematopoietic compartment results in a progressive loss of long-term hematopoietic stem cells (LT-HSCs) that is associated with concomitant reduction in their quiescence, leading to a defect in the maintenance of self-renewal as assessed by serial transplantation. Transcriptional profiling revealed that multiple stem cell maintenance factors are perturbed in Pbx1-deficient LT-HSCs, which prematurely express a large subset of genes, including cell-cycle regulators, normally expressed in non-self-renewing multipotent progenitors. A significant proportion of Pbx1-dependent genes is associated with the TGF-beta pathway, which serves a major role in maintaining HSC quiescence. Prospectively isolated, Pbx1-deficient LT-HSCs display altered transcriptional responses to TGF-beta stimulation in vitro, suggesting a possible mechanism through which Pbx1 maintenance of stem cell quiescence may in part be achieved.

Pubmed ID: 18462698

Authors

  • Ficara F
  • Murphy MJ
  • Lin M
  • Cleary ML

Journal

Cell stem cell

Publication Data

May 8, 2008

Associated Grants

  • Agency: NCI NIH HHS, Id: CA42971
  • Agency: NCI NIH HHS, Id: CA90735
  • Agency: NCI NIH HHS, Id: R01 CA090735
  • Agency: NCI NIH HHS, Id: R01 CA090735-06
  • Agency: NCI NIH HHS, Id: R01 CA090735-07
  • Agency: NCI NIH HHS, Id: R01 CA090735-08

Mesh Terms

  • Animals
  • Cell Count
  • Cell Cycle
  • Cell Lineage
  • Cell Proliferation
  • DNA-Binding Proteins
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells
  • Mice
  • Mice, Knockout
  • Proto-Oncogene Proteins
  • Signal Transduction
  • Transforming Growth Factor beta