Roadkill attenuates Hedgehog responses through degradation of Cubitus interruptus
2006
The final step in Hedgehog (Hh) signal transduction is post-translational
regulation of the transcription factor, Cubitus interruptus (Ci). Ci resides
in the cytoplasm in a latent form, where Hh regulates its processing into a
transcriptional repressor or its nuclear access as a transcriptional
activator. Levels of latent Ci are controlled by degradation, with different
pathways activated in response to different levels of Hh. Here, we describe
the roadkill ( rdx ) gene, which is expressed in response to
Hh. The Rdx protein belongs to a conserved family of proteins that serve as
substrate adaptors for Cullin3-mediated ubiquitylation. Overexpression of
rdx reduced Ci levels and decreased both transcriptional activation
and repression mediated by Ci. Loss of rdx allowed excessive
accumulation of Ci. rdx manipulation in the eye revealed a novel role
for Hh in the organization and survival of pigment and cone cells. These
studies identify rdx as a limiting factor in a feedback loop that
attenuates Hh responses through reducing levels of Ci. The existence of human
orthologs for Rdx raises the possibility that this novel feedback loop also
modulates Hh responses in humans.
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