Mutations in Sonic Hedgehog (SHH) signaling pathway genes, for example, Suppressor of Fused (SUFU), drive granule neuron precursors (GNP) to form medulloblastomas (MB^SHH). However, how different molecular lesions in the Shh pathway drive transformation is frequently unclear, and SUFU mutations in the cerebellum seem distinct. In this study, we show that fibroblast growth factor 5 (FGF5) signaling is integral for many infantile MB^SHH cases and that FGF5 expression is uniquely upregulated in infantile MB^SHH tumors. Similarly, mice lacking SUFU (Sufu-cKO) ectopically express Fgf5 specifically along the secondary fissure where GNPs harbor preneoplastic lesions and show that FGFR signaling is also ectopically activated in this region. Treatment with an FGFR antagonist rescues the severe GNP hyperplasia and restores cerebellar architecture. Thus, direct inhibition of FGF signaling may be a promising and novel therapeutic candidate for infantile MB^SHH.

Speech comprehension involves the dynamic interplay of multiple cognitive processes, from basic sound perception, to linguistic encoding, and finally to complex semantic-conceptual interpretations. How the brain handles the diverse streams of information processing remains poorly understood. Applying Hidden Markov Modeling to fMRI data obtained during spoken narrative comprehension, we reveal that the whole brain networks predominantly oscillate within a tripartite latent state space. These states are, respectively, characterized by high activities in the sensory-motor (State #1), bilateral temporal (State #2), and default mode networks (DMN; State #3) regions, with State #2 acting as a transitional hub. The three states are selectively modulated by the acoustic, word-level semantic, and clause-level semantic properties of the narrative. Moreover, the alignment with both the best performer and the group-mean in brain state expression can predict participants’ narrative comprehension scores measured from the post-scan recall. These results are reproducible with different brain network atlas and generalizable to two datasets consisting of young and older adults. Our study suggests that the brain underlies narrative comprehension by switching through a tripartite state space, with each state probably dedicated to a specific component of language faculty, and effective narrative comprehension relies on engaging those states in a timely manner.