Stem Cells

TOR Inhibition Promotes Self-Renewal

Science Signaling  27 Jul 2010:
Vol. 3, Issue 132, pp. ec231
DOI: 10.1126/scisignal.3132ec231

Germline stem cells (GSCs) in the female fruit fly divide asymmetrically to produce a GSC and the cystoblast that will differentiate into an oocyte and its associated support cells. GSC self-renewal requires bone morphogenetic protein (BMP) signaling, which represses transcription of the differentiation factor bag of marbles (bam). Sun et al. report that the tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2, plays an important role in GSC maintenance by preventing GSC differentiation through repression of the target of rapamycin (TOR) signaling complex TORC1. Clonal analysis in the female germline revealed that GSCs that were homozygous for a null mutation in either Tsc1 or Tsc2 failed to be maintained and instead differentiated prematurely. Treatment with the TORC1 inhibitor rapamycin rescued Tsc1 GSC depletion, and mutation of S6k, which encodes a ribosomal kinase activated by TORC1, rescued Tsc2 GSC depletion in Tsc2 mutant, indicating that TSC repressed GSC differentiation through TORC1 inhibition. As compared with WT GSCs, Tsc1 mutant GSCs exhibited decreased BMP signaling but did not show loss of bam transcriptional repression, and mutation of bam did not rescue the loss of Tsc1 in GSCs. Whereas bam mutant GSCs underwent no differentiation, bam Tsc1 double-mutant GSCs partially differentiated, implying that TSC1 repressed GSC differentiation independently of Bam. Curiously, although hyperactivation of TORC1 by removing TSC activity inhibited BMP signaling and GSC maintenance, TOR was not required for normal BMP signaling or germline differentiation. However, TOR was required for cell growth and survival in the germline, consistent with its function in other tissues. The authors propose a model in which TSC promotes self-renewal of GSCs by both BMP-Bam–dependent and –independent pathways, and they propose that the BMP-independent mechanism may involve regulating the translation of mRNAs that encode differentiation factors.

P. Sun, Z. Quan, B. Zhang, T. Wu, R. Xi, TSC1/2 tumour suppressor complex maintains Drosophila germline stem cells by preventing differentiation. Development 137, 2461–2469 (2010). [Abstract] [Full Text]