Fine-Tuning of Shh/Gli Signaling Gradient by Non-proteolytic Ubiquitination during Neural Patterning

Sonic Hedgehog (Shh) signaling plays crucial roles in patterning the ventral neural tube, which is transformed into opposing gradients of repressor and activator forms of Glis. Here, we show that the fine-tuning of the shape of the Gli gradients through non-proteolytic ubiquitination-mediated nuclear exportation plays an important role in the control of local neural cell fate. Loss of RNF220, a ventral neural-specific ubiquitin E3 ligase, leads to ventral expansion of the intermediate V0 and dorsal expansion of the ventral V3 neurons, while reducing the V1, V2, and motor neurons between them. We show that RNF220 interacts with all Glis, either in their activator or repressor forms; induces their K63-linked ubiquitination; and promotes their nuclear export, likely by unmasking a nuclear export signal in the zinc finger domain. We propose that RNF220 works to refine the Gli gradients during neural patterning by limiting the effective Gli levels in the nucleus.