Plzf Regulates Germline Progenitor Self-Renewal by Opposing mTORC1

Cell. 2010 Aug 6;142(3):468-79. doi: 10.1016/j.cell.2010.06.041.

Abstract

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.

Publication types

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

MeSH terms

  • Animals
  • Feedback, Physiological
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / metabolism
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • Male
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes
  • Promyelocytic Leukemia Zinc Finger Protein
  • Proteins
  • Signal Transduction
  • Spermatogonia / cytology*
  • Spermatogonia / metabolism
  • Stem Cells / cytology*
  • Stem Cells / metabolism
  • TOR Serine-Threonine Kinases
  • Testis / cytology
  • Transcription Factors / metabolism*

Substances

  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Kruppel-Like Transcription Factors
  • Multiprotein Complexes
  • Promyelocytic Leukemia Zinc Finger Protein
  • Proteins
  • Transcription Factors
  • Zbtb16 protein, mouse
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1