β-Arrestin-1 links mitogenic sonic hedgehog signaling to the cell cycle exit machinery in neural precursors

Development of the cerebellum, a brain region regulating posture and coordination, occurs post-natally and is marked by rapid proliferation of granule neuron precursors (CGNPs), stimulated by mitogenic Sonic hedgehog (Shh) signaling. beta-Arrestin (beta Arr) proteins play important roles downstream of Smoothened, the Shh signal transducer. However, whether Shh regulates beta Arrs and what role they play in Shh-driven CGNP proliferation remains to be determined. Here, we report that Shh induces beta Arr1 accumulation and localization to the nucleus, where it participates in enhancing expression of the cyclin dependent kinase (cdk) inhibitor p27, whose accumulation eventually drives CGNP cell cycle exit. beta Arr1 knockdown enhances CGNP proliferation and reduces p27 expression. Thus, Shh-mediated beta Arr1 induction represents a novel negative feedback loop within the Shh mitogenic pathway, such that ongoing Shh signaling, while required for CGNPs to proliferate, also sets up a cell-intrinsic clock programming their ultimate exit from the cell cycle.