Wnt and mTOR Signaling Team Up to Control Primary Cilia Formation in Human Cells

Primary cilia are slender, microtubule-based projections that function as cellular antennae, transducing signals from Hedgehog, Wnt, TGF-β, and other pathways. Defective cilia cause ciliopathies—a broad class of diseases involving retinal degeneration, kidney cysts, and skeletal malformations. Although cilia are known to influence signaling, how signaling pathways in turn regulate cilia formation remains poorly understood.

This study by Yuan and colleagues used human retinal pigment epithelial (hTERT-RPE1) cells—a well-established model for ciliogenesis—to dissect how modulating Wnt/LRP6 signaling affects primary cilia assembly. The team first confirmed that basal Wnt/β-catenin activity is required for ciliation: siRNA knockdown of LRP5/6 or β-catenin reduced cilia frequency by 30–50%, without substantially shortening the cilia that did form. This suggests Wnt/β-catenin selectively controls cilia initiation rather than elongation.

To examine the effect of elevated Wnt activity, the researchers pre-treated cells with Wnt3a-conditioned medium or the Wnt agonist CHIR99021 before serum starvation. Both interventions significantly delayed ciliogenesis. Mechanistic analysis revealed multiple converging defects: (1) distal appendage components showed dysregulation, (2) the inhibitory CP110-CEP97 cap was not properly removed from mother centrioles, (3) Rab8-positive vesicle docking at the centriole was reduced, and (4) centriolar satellite-associated OFD1—another ciliogenesis inhibitor—remained elevated. Together, these failures block both ciliary membrane establishment and axoneme extension.

The study then asked why OFD1 persisted at centriolar satellites. Normally, OFD1 is cleared by autophagy at the onset of ciliogenesis. Cells with elevated Wnt activity displayed reduced autophagic flux and increased mTOR kinase activity, consistent with the known Wnt/mTOR arm in which Wnt inhibits GSK3-dependent activation of the mTORC1 suppressor TSC2. Critically, pharmacological inhibition of mTOR with rapamycin or Torin-1 rescued ciliogenesis in Wnt-hyperactivated cells, and ectopic removal of OFD1 produced a similar rescue, linking excessive mTOR activity and OFD1 accumulation as the key downstream effectors of Wnt-driven ciliogenesis impairment.

Collectively, the data support a model in which Wnt signaling operates within a precise window: insufficient Wnt reduces cilia initiation, while excessive Wnt suppresses autophagy via mTOR, allowing OFD1 to accumulate at centriolar satellites and block cilia assembly. The interplay between Wnt and mTOR thus acts as a rheostat for ciliogenesis, with implications for understanding ciliopathies and diseases in which Wnt or mTOR are dysregulated, including cancer and age-related degenerative conditions.