Suppression of Hedgehog signaling by Cul3 ligases in proliferation control of retinal precursors.

Cullin-RING ubiquitin ligases ubiquitinate protein substrates and control their levels through degradation. Here we show that cullin3 (Cul3) suppresses Hedgehog (Hh) signaling through downregulating the level of the signaling pathway effector cubitus interruptus (Ci). High-level Hh signaling promotes Cul3-dependent Ci degradation, leading to the downregulation of Hh signaling. This process is manifested in controlling cell proliferation during Drosophila retinal development. In Cul3 mutants, the population of interommatidial cells is increased, which can be mimicked by overexpression of Ci and suppressed by depleting endogenous Ci. Hh also regulates the population of interommatidial cells in the pupal stage. Alterations in the interommatidial cell population correlate with alterations in precursor proliferation in the second mitotic wave of larval eye discs. Taken together, these results suggest that Cul3 downregulates Ci levels to modulate Hh signaling activity, thus ensuring proper cell proliferation during retinal development.