(A) In the absence of Wnt stimuli, β-catenin is constitutively phosphorylated by the β-catenin destruction complex consisting of Axin, APC, and GSK3β. Phosphorylated β-catenin is targeted for degradation. Wnt targets are repressed by a complex of TCF/LEF1 and TLE. In canonical Wnt signaling, the ligand binds to a complex of the Frizzled receptor and LRP5/6 coreceptor, which then binds to Axin and Dishevelled (DVL), leading to stabilization of β-catenin in the cytoplasm. β-catenin migrates into the nucleus, replaces TLE, and activates transcription ofβ-catenin/TCF/LEF1-responsive genes. In noncanonical signaling, activated DVL is targeted to the membrane and activates downstream targets.
(B) Effects of ciliary and basal body disruption on Wnt signaling. In ciliated cells, noncanonical Wnt signals antagonize canonical Wnt signaling, leading to proteasomal β-catenin degradation and membrane targeting of DVL. In unciliated cells, canonical Wnt signaling stabilizes cytoplasmic β-catenin and DVL, leading to increased nuclear levels of both DVL and β-catenin, initiating transcription of TCF/LEF1-responsive genes. Disruption of ciliary or basal body components leads to loss of noncanonical Wnt signaling and stabilization of both DVL and β-catenin in the cytoplasm and nucleus, resembling the status of nonciliated cells.
(C) In the absence of sonic hedgehog (Shh) ligand, Patched (Ptch) represses Smoothened (Smo). Repressive forms of the Gli proteins bind to the promoter regions of Shh targets and inhibit transcription. Stimulation with Shh ligand recruits Smo and Ptch1 to the primary cilium. Gli2 and Gli3 are localized to both the cilium and the nucleus, and in response to the ligand stimulus they are proteasomally processed into their activator Gli2/3A isoforms, activating transcription of Shh targets.
(D) Differential role of ciliary and basal body proteins in Gli2/3 processing. Perturbation of anterograde intraflagellar transport (IFT) leads to loss of Gli2 and Gli3 processing and Shh signaling. Loss of structural integrity of the primary cilium by disruption of Arl13b leads to constitutively active Gli2, but leaves Gli3 unaffected. Loss of retrograde IFT triggers both Gli2 and Gli3 proteasomal activation along with transcriptional upregulation of Gli3. Finally, disruption of the basal body does not affect Gli2 processing but increases both expression and proteasomal activation of Gli3.