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How the Gli2 Transcription Factor Gets to the Cilium Tip for Hedgehog Signaling
The primary cilium acts as a hub for several signal-transduction pathways, including the essential vertebrate Hedgehog (Hh) pathway. The Intraflagellar Transport (IFT) system is required for building the cilium, and defects in IFT result is aberrant Hh signaling. Critical to Hh activation is the localization of the Gli transcription factor at the cilium's distal tip. Despite its significance, the mechanisms that transport Gli molecules within the cilium remains elusive. We developed a live-cell imaging assay utilizing TIRF microscopy to visualize Gli2 molecules within the cilium. We find that the concentration of Gli2 at the cilium tip represents an early event in Hh signaling. High temporalresolution imaging revealed that Gli2 is an IFT cargo, and Gli2 transport by IFT is highly temporally regulated, peaking within the initial hour post-pathway activation. Furthermore, we find that Kif7, a non-motile ciliary kinesin and Gli2 binding protein, is a key regulator of IFT-mediated Gli2 trafficking. This discovery underscores the collaborative role of distinct cilium-specific cytoskeletal systems in facilitating Hhresponsive Gli2 trafficking. Our findings unveil a broader role for IFT in vertebrate Hh signaling, positioning it as a crucial participant in Gli transport beyond cilium architecture maintenance.
Speakers
Radhika Subramanian