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.
Ou
Chan-Yen
CY
Taiwan International Graduate Program, Graduate Institute of Life Science, National Defense Medical Center and Academia Sinica, Taipei, Taiwan.
Wang
Chien-Hsiang
CH
Jiang
Jin
J
Chien
Cheng-Ting
CT
D000818:Animals; D030801:Animals, Genetically Modified; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004330:Drosophila / Q000166:cytology / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D012160:Retina / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; C503647:Cul3 protein, Drosophila; D044842:Cullin Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D014157:Transcription Factors; C092937:ci protein, Drosophila; C077245:hh protein, Drosophila