Graduate program, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
Development. 2010 Aug 1;137(15):2461-9. doi: 10.1242/dev.051466. Epub 2010 Jun 23.
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.
结节性硬化症复合体人类疾病基因产物 TSC1 和 TSC2 形成一个功能复合物,负调控雷帕霉素靶蛋白(TOR),TOR 是一种进化上保守的激酶,在细胞生长和代谢中发挥核心作用。在这里,我们描述了 TSC1/2 控制干细胞维持的新作用。我们表明,在果蝇卵巢中,生殖干细胞(GSCs)中 Tsc1 或 Tsc2 基因的破坏导致 GSC 过早分化和丢失。用 TORC1 抑制剂雷帕霉素或消除 TORC1 的下游效应物 S6K 处理可以挽救 GSC 丢失,表明 Tsc1/2 突变 GSC 的过早分化是由于 TORC1 的过度激活。维持 GSC 的一个众所周知的机制是,来自巢的 BMP 信号直接抑制 GSCs 中促进分化的基因 bag of marbles(bam)的表达。在 Tsc1/2 突变 GSCs 中,BMP 信号活性下调,但 bam 表达仍被抑制。此外,Tsc1 bam 双突变 GSCs 可以分化为早期囊细胞,表明 TSC1/2 通过 BMP-Bam 依赖和非依赖途径控制 GSC 分化。总之,这些结果表明,TSC 通过抑制 TORC1 活性和随后的促分化程序来防止 GSC 过早分化。由于 TSC1/2-TORC1 信号在从果蝇到哺乳动物中高度保守,它可能在控制哺乳动物包括人类中的干细胞行为方面具有类似的作用。