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Suppressor of Fused (Sufu) controls cerebellum granule cell proliferation by suppressing Fgf8 and spatially regulating Gli proteins.

Cerebellar granule cell (GC) development relies on precise regulation of Sonic Hedgehog (Shh)-Gli signaling activity, failure of which is associated with motor disorders and medulloblastoma. Mutations in pathway regulator Sufu, which modulates Gli activators and repressors, are linked to cerebellar dysfunction and tumourigenesis. The mechanism by which Sufu calibrates Shh signaling in GCs is un known. Math1-Cre-mediated deletion of Sufu in GC progenitors (GCPs) demonstrated that Sufu restricts GCP proliferation and promotes cell cycle exit, by promoting expression of Gli3R and suppressing Gli2 levels. Sufu is also required to promote high threshold of pathway activity in GCPs. Remarkably, central cerebellar lobules are more deleteriously impacted by Sufu deletion, but are less sensitive to downstream genetic manipulations to reduce Gli2 expression or overexpress a Gli3R mimic, compared to anterior lobules. Transcriptome sequencing uncovered new Sufu targets, especially Fgf8, which is upregulated in Sufu-mutant GCPs. We demonstrated that Fgf8 is necessary and sufficient to drive Sufu-mutant GCP proliferation. This study reveals new insights into the spatial and temporal regulation of cerebellar Shh-Gli signalling, while uncovering new targets such as Fgf8.