Suppressor of fused 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 signalling activity, failure of which is associated with motor disorders and medulloblastoma. Mutations in the pathway regulator suppressor of fused (Sufu), which modulates Gli activators and repressors, are linked to cerebellar dysfunction and tumourigenesis. The mechanism by which Sufu calibrates Shh signalling in GCs is unknown. Math1-Cre-mediated deletion of Sufu in mouse 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 a 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 with anterior lobules. Transcriptome sequencing uncovered new Sufu targets, especially Fgf8, which is upregulated in Sufu-mutant GCPs. We demonstrate 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.
['Jiwani|Tayyaba|T|', 'Kim|Jinny J|JJ|0000-0002-2799-7053', 'Rosenblum|Norman D|ND|0000-0003-1767-6464']
D000818:Animals D002453:Cell Cycle D049109:Cell Proliferation D002531:Cerebellum D005260:Female D051524:Fibroblast Growth Factor 8 D018507:Gene Expression Regulation, Developmental D053823:Hedgehog Proteins D008297:Male D051379:Mice D008822:Mice, Transgenic D009419:Nerve Tissue Proteins D009474:Neurons D012097:Repressor Proteins D015398:Signal Transduction D059467:Transcriptome D000075746:Zinc Finger Protein Gli2 D000074290:Zinc Finger Protein Gli3
Cerebellum development Granule neurons Sonic hedgehog signalling Spatial patterning Sufu-Gli regulation