Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration

Cell Rep. 2016 Nov 1;17(6):1584-1594. doi: 10.1016/j.celrep.2016.10.025.

Abstract

Imprinted genes are differentially expressed by adult stem cells, but their functions in regulating adult stem cell fate are incompletely understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an imprinted gene, regulates hematopoietic stem cell (HSC) self-renewal and regeneration. Deletion of the maternal allele of Grb10 in mice (Grb10m/+ mice) substantially increased HSC long-term repopulating capacity, as compared to that of Grb10+/+ mice. After total body irradiation (TBI), Grb10m/+ mice demonstrated accelerated HSC regeneration and hematopoietic reconstitution, as compared to Grb10+/+ mice. Grb10-deficient HSCs displayed increased proliferation after competitive transplantation or TBI, commensurate with upregulation of CDK4 and Cyclin E. Furthermore, the enhanced HSC regeneration observed in Grb10-deficient mice was dependent on activation of the Akt/mTORC1 pathway. This study reveals a function for the imprinted gene Grb10 in regulating HSC self-renewal and regeneration and suggests that the inhibition of Grb10 can promote hematopoietic regeneration in vivo.

Keywords: adaptor protein; hematopoietic stem cells; imprinted gene; regeneration; self-renewal.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Cell Proliferation
  • Cell Self Renewal / genetics*
  • GRB10 Adaptor Protein / deficiency*
  • GRB10 Adaptor Protein / metabolism
  • Gene Deletion*
  • Genomic Imprinting*
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice, Inbred C57BL
  • Proto-Oncogene Proteins c-akt / metabolism
  • Regeneration*
  • Signal Transduction
  • Whole-Body Irradiation

Substances

  • Grb10 protein, mouse
  • GRB10 Adaptor Protein
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt