TSC1/2 tumour suppressor complex maintainsDrosophilagermline stem cells by preventing differentiation

Abstract

SUMMARYTuberous sclerosis complex human disease gene products TSC1 and TSC2 form a functional complex that negatively regulates target of rapamycin (TOR), an evolutionarily conserved kinase that plays a central role in cell growth and metabolism. Here, we describe a novel role of TSC1/2 in controlling stem cell maintenance. We show that in the Drosophila ovary, disruption of either the Tsc1 or Tsc2 gene in germline stem cells (GSCs) leads to precocious GSC differentiation and loss. The GSC loss can be rescued by treatment with TORC1 inhibitor rapamycin, or by eliminating S6K, a TORC1 downstream effecter, suggesting that precocious differentiation of Tsc1/2 mutant GSC is due to hyperactivation of TORC1. One well-studied mechanism for GSC maintenance is that BMP signals from the niche directly repress the expression of a differentiation-promoting gene bag of marbles (bam) in GSCs. In Tsc1/2 mutant GSCs, BMP signalling activity is downregulated, but bam expression is still repressed. Moreover, Tsc1 bam double mutant GSCs could differentiate into early cystocytes, suggesting that TSC1/2 controls GSC differentiation via both BMPBam-dependent and -independent pathways. Taken together, these results suggest that TSC prevents precocious GSC differentiation by inhibiting TORC1 activity and subsequently differentiation-promoting programs. As TSC1/2-TORC1 signalling is highly conserved from Drosophila to mammals, it could have a similar role in controlling stem cell behaviour in mammals, including humans.

TSC1/2 regulates intestinal stem cell maintenance and lineage differentiation via Rheb-TORC1-S6K but independent of nutrition status or Notch regulation

“…A similar role for stem cell maintenance was observed for Drosophila ovarian GSCs and mammalian hematopoietic stem cells, although the underlying mechanisms could be different (LaFever et al, 2010;Sun et al, 2010). For example, DE-cadherin expression was not altered in Tsc1/2 mutant germline stem cells (Sun et al, 2010), or in Tsc1/2 mutant imaginal disc cells (supplementary material Fig.…”

Insulin and Target of rapamycin signaling orchestrate the development of ovarian niche-stem cell units in Drosophila

“…The ovary is an active organ that maintains growing populations of cells. Accordingly, in the adult, somatic follicle cells, GSCs and germline cysts respond to nutrition by changing their proliferation rate (Drummond-Barbosa and Spradling, 2001;LaFever and Drummond-Barbosa, 2005;LaFever et al, 2010;Sun et al, 2010). InR signaling cell-autonomously regulate the proliferation of both PGCs and somatic niche precursors (green arrows).…”

“…In C. elegans these pathways promote germ cell proliferation, repress precocious germ cell differentiation and participate in the establishment of an appropriately sized progenitor pool (Korta et al, 2012;Michaelson et al, 2010). In the Drosophila ovary, Insulin-like peptides (DILPs) directly regulate germline stem cell (GSC) division, cyst growth and vitellogenesis, while Tor is required for proper proliferation, maintenance and growth of GSCs and early cysts (Drummond-Barbosa and Spradling, 2001;LaFever and Drummond-Barbosa, 2005;LaFever et al, 2010;Richard et al, 2005;Sun et al, 2010). Insulin signaling also controls GSC maintenance indirectly by promoting niche cell maintenance via Notch signaling and niche-GSC interaction via E-Cadherin (Hsu and Drummond-Barbosa, 2009;Hsu and Drummond-Barbosa, 2011).…”

Adipocyte amino acid sensing controls adult germline stem cell number via the amino acid response pathway and independently of Target of Rapamycin signaling in Drosophila

“…On a yeast-rich diet, GSCs and their progeny grow and proliferate faster than on a yeast-free diet (DrummondBarbosa and Spradling, 2001), and this response is mediated by diet-dependent factors that act on or within the ovary. For example, optimal levels of Target of Rapamycin (TOR) activity likely controlled by circulating amino acids are intrinsically required in GSCs for their proliferation and maintenance (LaFever et al, 2010;Sun et al, 2010). Insulin-like peptides produced by median neurosecretory cells in the brain act directly on GSCs to modulate how fast they proliferate to generate new cystoblasts (LaFever and Drummond-Barbosa, 2005;Hsu et al, 2008).…”