Roles Of Leucine-rich Glioma Inactived 1 (LGI1) In The Development Of Mouse Cerebellum And Myelination

Leucine-rich glioma inactivated 1 (LGI1) is a secreted protein that interacts with (a disintegrin and metalloproteinase) ADAM transmembrane proteins, and its mutations are linked to human epilepsy. The function of LGI1 in CNS development remains undefined. Here, we report novel functions of LGI1 in the generation of cerebellar granule precursors (CGPs) and differentiation of radial glial cells (RGCs) in the cerebellum. A reduction in external granule layer thickness and defects in foliation were seen in embryonic and new-born LGI1 knockout (KO) mice. BrdU staining showed an inhibited proliferation of CGPs in KO embryos, which might be explained by the reduced Sonic hedgehog in embryos. In addition, the differentiation of RGCs into Bergmann glia was suppressed in KO mice. Enhanced Jagged 1-Notch 1 signaling in KO mice via reduced β-secretase proteolysis suggests that altered phenotype of RGCs is due to abnormal Notch 1 signaling.Moreover,we find another function of LGI1 in the myelination of Central Nervous System (CNS) and Peripheral Nervous System (PNS). Reductions in myelin sheats, the number of myelinated axons were seen using electron microscopy, the expression of myelin associated proteins had been found in KO mice. We further found that LGI1 ablation in vivo, LGI1-knockdown and overexpression in vitro impaired differentiation of OPCs (oligodendrocyte precursor cells) to mature oligodendrocytes, but not the proliferation. In addition, Lgi1+/- mice display severer damage in cuprizone-induced demyelination. Meanwhile, reductions in myelin sheats, increased incidence of looser organization of myelin layers were seen in PNS of the ko mice. Finally, we found that these myelin deficits were ascribed to the down-regulation of lipogenic metabolism mediated by the over-activation of mTORCl in oligodendrocytes and the reduction of tuberous sclerois complex 1 (TSC1)Together, our results demonstrate that LGI1 is an essential player in the development of cerebellum and myelination.