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Development 137 (15): 2461-2469

DEVELOPMENT AND STEM CELLS

TSC1/2 tumour suppressor complex maintains Drosophila germline stem cells by preventing differentiation

Pei Sun1,2, Zhenghui Quan2, Bodi Zhang2, Tuoqi Wu2, and Rongwen Xi2,*

1 Graduate program, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
2 National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.

* Author for correspondence (xirongwen{at}nibs.ac.cn)

Accepted for publication 18 May 2010.

Abstract: Tuberous 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 BMP-Bam-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.

Key Words: Drosophila ovary • Target of rapamycin • Tuberous sclerosis complex • Differentiation • Germline stem cell • Maintenance

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