Plzf Regulates Germline Progenitor Self-Renewal by Opposing mTORC1

Abstract

SUMMARY 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.

Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function

“…PLZF possesses both transcriptional activation and repression functions. It promotes redd1 and maf but suppresses gfi1 transcription (20,23,24). Using ChIP and quantitative real-time PCR (qRT-PCR), we found diminished association of PLZF protein with gfi1, redd1, maf, and myc promoters in rapamycintreated PLZF-3C3 cells compared with mock-treated cells (Fig.…”

“…and mTORC1 playing important roles. Additionally, PLZF can oppose mTORC1 activity through the induction of Redd1 (23). PLZF may function as a negative feedback mechanism to dampen mTORC1 activation.…”

Pluripotency of Male Germline Stem Cells

“…Transplantation experiments have shown that Plzf -/-recipient mice normally support self-renewal and differentiation of Plzf +/+ germ cells, implying that a lack of Plzf causes a severely degenerating phenotype only in germ cells and not in Sertoli cells (Buaas et al, 2004;Costoya et al, 2004). Plzf regulates the self-renewal of spermatogonial progenitor cells by counteracting mTORC1 via induction of the mTOR1 inhibitor Redd1 (Hobbs et al, 2010).…”

Stem-ing mTOR: p53 maintains the male germline

“…Moreover, spermatogonial differentiation is promoted by mTORC1 activity, a mechanism that can be completely disrupted by the chronic exposure of testes to rapamycin. 2,7 The balance of stem cell self-renewal and differentiation therefore appears to be regulated by the relative activities of p53 and mTORC1, which are subjected to alteration during aging, cancer and other biological phenomena. The research findings and novel FACSbased approach from Xiong et al 5 should open up new lines of inquiry into the molecular mechanisms of male germline stem cell differentiation.…”

“…2 Loss of functional Plzf in male mice results in germ cell depletion due to insufficient stem cell self-renewal. 3,4 mTORC1 is negatively regulated by p53 following DNA damage in multiple cell types to allow for repair in a quiescent, low metabolic environment, but whether this mechanism regulates the balance of germline stem cell self-renewal and differentiation was not known until now.…”