Improved ER quality control alleviates dysplasia of aging ISCs.

<p>(A) Intestines of wild-type flies stained with anti-bGal antibodies at 5 days or 33 days of age and of old flies over-expressing Hrd1 or Xbp1 (Xbp1^d08698) in ISCs/EBs (esg::Gal4) and carrying the gstD1::lacZ reporter. Arrowheads point to ISCs/EBs (marked by GFP). Quantification of relative bGal staining shown in the right panel. Ratio of fluorescence intensity in ISCs/EBs and nearby ECs is shown. ISCs/EBs identified by GFP. P values from Student's T test. N> = 3. (B) Quantification of mitotic figures in aging wild-type flies and in flies expressing Xbp1 (Xbp1^d08698, Xbp1^EP2112) and Hrd1 in ISCs/EBs (esg::Gal4, UAS::GFP). Averages and SEM are shown. P values from Student's T test, N>160 (from 4–5 guts each). N>20(5 d), N>20 (25 d), N>25 (35 d), N>7 (45 d), n>14 (55d)) (C) Model of UPR^ER/ROS signaling network regulating ISC proliferation, through ER stress is required for the induction of ISC proliferation. Inhibition of CncC activity by JNK in response to ER-induced ROS is further required to permit ISC regenerative responses. (D) Age-related loss of proliferative homeostasis as a consequence of increased ER stress. See also <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004568#pgen.1004568.s005" target="_blank">Figure S5</a>.