Regulation of FGF/MAPK signaling at the primary cilium base controls the proliferation-neurogenesis balance in human cerebellar organoids

RPGRIP1L-deficient human cerebellar organoids show a consistent severe loss of Purkinje cell markers linked to impaired neurogenesis, increased progenitor proliferation, and prolonged FGF/MAPK overactivation.

• Why it matters: Ciliary dysfunction in Joubert syndrome is linked to cerebellar hypoplasia and dysplasia, but how the primary cilium regulates developmental FGF/MAPK signaling in human cerebellar progenitors is unclear.
• What they did: The study generated cerebellar organoids with null or patient-derived RPGRIP1L mutations, assessed lineage and proliferation, mapped pMEK1/2 at the primary cilium base, and tested FGF receptor inhibition to reduce pMEK1/2 activation.
• The result: FGF receptor inhibition reduced pMEK1/2 activation at the cilia base and rescued the proliferation–neurogenesis imbalance and Purkinje lineage defects in RPGRIP1L-deficient progenitors, without restoring ciliary abnormalities.

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