Amcheslavsky et al. reveal that Drosophila intestinal stem cells lacking the tuberous sclerosis complex (TSC) grow too large to divide, resulting in defective gut epithelia.
TSC is a complex of two proteins that prevents the activation of the growth-promoting kinase target of rapamycin (TOR). TSC1 and TSC2 are considered to be tumor suppressors because they restrict cell growth and proliferation in tissues such as Drosophila imaginal discs. Amcheslavsky et al. identified TSC2 in a screen for regulators of adult intestinal stem cells. Gut precursors lacking TSC1 or TSC2 grew up to ten times larger than wild-type stem cells, but they failed to undergo cell division. TSC-deficient fly intestines had a thinner epithelial lining and were more sensitive to tissue-damaging agents such as bleomycin, presumably because injured cells could not be replaced by the daughters of mutant intestinal stem cells.
This unexpected defect in proliferation was caused by the stem cells’ excessive growth. Feeding flies with the TOR inhibitor rapamycin or depleting the transcription factor Myc suppressed growth and restored normal rates of proliferation to intestinal stem cells lacking TSC.
It's unclear why TSC deficiency blocks the division of intestinal stem cells but stimulates the proliferation of other cell types. One possibility, says senior author Tony Ip, is that cells in imaginal discs and other developing tissues proliferate so rapidly that they can't grow big enough to block division. Adult intestinal stem cells cycle slowly, however, and may therefore be more sensitive to changes in cell growth rates.