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

Sirolimus 0301 basic medicine Stem Cells TOR Serine-Threonine Kinases Intracellular Signaling Peptides and Proteins Apoptosis Cell Cycle Proteins Cell Differentiation Protein Serine-Threonine Kinases Models, Biological 03 medical and health sciences Drosophila melanogaster Germ Cells Microscopy, Fluorescence Bone Morphogenetic Proteins Mutation Animals Drosophila Proteins Crosses, Genetic
DOI: 10.1242/dev.051466 Publication Date: 2010-06-24T00:59:18Z
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.
SUPPLEMENTAL MATERIAL
Coming soon ....
REFERENCES (42)
CITATIONS (69)
EXTERNAL LINKS
PlumX Metrics
RECOMMENDATIONS
FAIR ASSESSMENT
Coming soon ....
JUPYTER LAB
Coming soon ....