TY - JOUR
T1 - Plzf regulates germline progenitor self-renewal by opposing mTORC1
AU - Hobbs, Robin M.
AU - Seandel, Marco
AU - Falciatori, Ilaria
AU - Rafii, Shahin
AU - Pandolfi, Pier Paolo
PY - 2010/8
Y1 - 2010/8
N2 - Hyperactivity of mTORC1, a key mediator of cell growth, leads to stem cell depletion, although the underlying mechanisms are poorly defined. Using spermatogonial progenitor cells (SPCs) as a model system, we show that mTORC1 impairs stem cell maintenance by a negative feedback from mTORC1 to receptors required to transduce niche-derived signals. We find that SPCs lacking Plzf, a transcription factor essential for SPC maintenance, have enhanced mTORC1 activity. Aberrant mTORC1 activation in Plzf -/- SPCs inhibits their response to GDNF, a growth factor critical for SPC self-renewal, via negative feedback at the level of the GDNF receptor. Plzf opposes mTORC1 activity by inducing expression of the mTORC1 inhibitor Redd1. Thus, we identify the mTORC1-Plzf functional interaction as a critical rheostat for maintenance of the spermatogonial pool and propose a model whereby negative feedback from mTORC1 to the GDNF receptor balances SPC growth with self-renewal.
AB - Hyperactivity of mTORC1, a key mediator of cell growth, leads to stem cell depletion, although the underlying mechanisms are poorly defined. Using spermatogonial progenitor cells (SPCs) as a model system, we show that mTORC1 impairs stem cell maintenance by a negative feedback from mTORC1 to receptors required to transduce niche-derived signals. We find that SPCs lacking Plzf, a transcription factor essential for SPC maintenance, have enhanced mTORC1 activity. Aberrant mTORC1 activation in Plzf -/- SPCs inhibits their response to GDNF, a growth factor critical for SPC self-renewal, via negative feedback at the level of the GDNF receptor. Plzf opposes mTORC1 activity by inducing expression of the mTORC1 inhibitor Redd1. Thus, we identify the mTORC1-Plzf functional interaction as a critical rheostat for maintenance of the spermatogonial pool and propose a model whereby negative feedback from mTORC1 to the GDNF receptor balances SPC growth with self-renewal.
KW - CELLBIO
KW - SIGNALING
KW - STEMCELL
UR - http://www.scopus.com/inward/record.url?scp=77955329636&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2010.06.041
DO - 10.1016/j.cell.2010.06.041
M3 - Article
C2 - 20691905
AN - SCOPUS:77955329636
VL - 142
SP - 468
EP - 479
JO - Cell
JF - Cell
SN - 0092-8674
IS - 3
ER -