Development:TSC1/2对维系果蝇生殖干细胞的重要作用
2010年6月23日,北京生命科学研究所袭荣文实验室在Development杂志上在线发表文章揭示结节性硬化症致病基因对维系果蝇生殖干细胞的重要作用。
结节性硬化症致病基因产物TSC1和TSC2具有在进化上高度保守的通过抑制TOR来控制细胞生长的功能。在这篇论文中,研究人员发现TSC1/2对维系果蝇生殖干细胞也起非常重要的作用。失去这些基因功能的生殖干细胞过早发生了分化,不能进行自我更新,从而导致干细胞的丢失。这种干细胞丢失现象可以被药物雷帕霉素(rapamycin)处理或S6k突变所抑制,说明干细胞丢失是由于TORC1的过过度激活导致的。在机制上,TORC1的过度激活可以抑制BMP信号通路在干细胞内的活性,而BMP信号是维系干细胞自我更新的主要因子。另外,TORC1的过度激活也可以激活一个不依赖BMP-BAM通路的分化途径,最终导致生殖干细胞的分化。
本论文揭示了结节性硬化症致病基因产物在干细胞调节中的一个新的,在进化上有可能保守的功能。这一新机制的发现有助于进一步理解干细胞在体内的自我更新与分化调节的平衡机制,并对理解结节性硬化症的病理及寻找防治措施具有参考作用。
北京生命科学研究所与协和联合招生研究生孙培为该论文的第一作者。其他作者还有研究生权争辉,毕设生张博迪和伍拓琦。袭荣文博士为论文通讯作者。此项研究为科技部和北京市科委资助课题,在北京生命科学研究所完成。
原文出处:
Development doi: 10.1242/dev.051466
TSC1/2 tumour suppressor complex maintains Drosophila germline stem cells by preventing differentiation
Pei Sun, Zhenghui Quan, Bodi Zhang, Tuoqi Wu and Rongwen Xi*
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.
编辑信箱
欢迎您推荐或发布各类关于实验动物行业资讯、研究进展、前沿技术、学术热点、产品宣传与产业资源推广、产业分析内容以及相关评论、专题、采访、约稿等。
我要分享 >热点资讯
- 年
- 月
- 周