UCLA

Imprinted genes have been shown to be differentially expressed by adult stem cells, but the function of imprinted genes in regulating adult stem cell fate is not well understood. Here, we show that growth factor receptor bound protein 10 (Grb10), a member of the imprinted gene family, 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 compared to Grb10+/+ mice. Furthermore, following total body irradiation (TBI), Grb10m/+ mice displayed accelerated HSC regeneration and overall hematopoietic reconstitution compared to Grb10+/+ mice. Grb10-deficient HSCs displayed increased migratory capacity and proliferative capacity in vivo following competitive transplantation or irradiation, commensurate with increased activation of the RhoGTPase, Rac1. Inhibition of Rac1 abrogated both the enhanced migratory capacity and the increased proliferative potential of Grb10-deficient HSCs in vivo. Grb10 has a long established role as a negative feedback inhibitor of Akt-mTOR signaling pathway. In accordance with this, our data show that inhibition of Akt-mTOR signaling pathway abolished the early regeneration of long-term HSCs in Grb10m/+ mice following irradiation, compared to Grb10+/+ mice. This study reveals a previously unrecognized role for the imprinted gene, Grb10, in regulating HSC self-renewal and regeneration and suggests that antagonism of Grb10 can promote hematopoietic regeneration in vivo.