Leucine-rich,glioma inactivated 1(LGI1)is a secreted neuronal protein that interacts with ADAM22/23 transmembrane proteins.Mutations in LGI1 are linked to human autosomal dominant lateral temporal lobe epilepsy.It has been shown that LGI1 prevents the inactivation of voltage-gated potassium channels,mediates postnatal maturation and pruning of glutamatergic synapses,and regulates excitatory neurotransmission.Here,we report unexpected functions of LGI1 in the development of mouse cerebellum.A reduction in external granule layer(EGL)thickness and foliation defect were seen in embryonic and newborn LGI1 knockout mice.However,the foliation of KO cerebella was grossly normal after P7,indicating that LGI1 knockout retards,but not prevents,the folia formation.While the production of neural stem cells was not affected,double staining with Pax6 and BrdU showed a significant inhibition of proliferation of granule cell precursors(GCPs)in EGL of knockout embryos.The decreased level of Shh might explain such abnormal proliferation of GCPs and foliation defect.Moreover,the differentiation of radial glial cells(RGCs)was suppressed in LGI1 knockout,as shown by increased BLBP-labeled RGCs and decreased GFAP-labeled Bergmann glias in vivo and in vitro.Finally,Western blots exhibited an enhanced Jagged1-Notch signaling activity in LGI null mice via reduced β-secretase-mediated proteolytic processing of Jagged1,showing that the altered phenotype of RGC may be ascribed to the suboptimal Notch1 signaling.Hence,our data demonstrated that LGI1,the human epilepsy-related protein,is also an essential player in the development of cerebellum.