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H. Ryoo, T. Gorenc, H. Steller. HHMI, Rockefeller Univ,
New York, NY.
Cell proliferation and death is tightly linked during animal
development. In Drosophila, cells doomed to die activate the
expression of reaper, hid and grim, which bind and inhibit the
essential anti-apoptotic protein, DIAP1. In imaginal discs, dying
cells are compensated by extra-proliferation, thereby maintaing
proper size during development. To test if this compensatory
proliferation is due to an active signaling activity from dying
cells, we generated diap1 -/- clones and rescued their lethality by
expressing the caspase inhibitor p35. Under these conditions,
overcompensation was observed where the surviving diap1 -/- cells
induced massive BrdU incorporation around them, thereby increasing
the size of imaginal discs. Similarly, inhibiting DIAP1 through
co-expression of hid and p35 led to overcompensation, indicating
that a signaling activity may persist by keeping these cells alive.
The effect on proliferation was dependent on the DIAP1
ubiquitin-ligase motif, as clones of diap1 alleles specifically
disrupting the RING domain also induced BrdU labeling. One
ubiquitylation target of DIAP1 is TRAF1 and the Jun-kinase pathway.
To test the role of the Jun-kinase pathway in compensatory
proliferation, we sensitized this pathway by reducing puckered
dosage, a negative regulator of Jun-kinase. Whereas expressing
reaper and p35 had minimal effect in BrdU incorporation, reaper and
p35 expression in puckered -/+ enhanced BrdU incorporation
non-autonomously. Our results support the model where cells
undergoing apoptosis inhibit DIAP1, thereby activating the Jun-kinase
pathway. This may induce mitogen expression that signal to
neighboring cells for compensatory proliferation. |
