The Role Of Joubert Syndrome Gene Arl13b In Cerebellar Development

Joubert syndrome is a kind of autosomal recessive genetic neural development disorder,which is characterized by the molar tooth sign,a complex malformation of the cerebellar vermis and brainstem with abnormalities of axonal decussation affecting the corticospinal tract and superior cerebellar peduncles.Arl13 b was identified as causative gene for the ciliopathy Joubert syndrome,which muted resulted in developmental defects selectively on the cerebellar vermis.Many studies revealed that Arl13 b has involved in the initial formation of the polarized radial progenitor scaffold,the migration and placement of interneurons,and other neural development.However,the precise function and roles of Arl13 b during early development of cerebellum still remain mystery.Here in,by using zebrafish as a model,we explores the role for Arl13 b in the early development of cerebellum.Our data revealed that zebrafish larvae mimic the phenotype of Joubert syndrome patients,and show impairment of balance and locomotion,and coupled defects in cerebellar structure after knockdown or knockout of Arl13 b.Analyzing the cerebellum in Arl13 b mutants and morphants revealed reduced the number of differentiated granule cells selectively in the medial subregions of the cerebellum along the midline.we also have observed that Arl13 b mutation also slightly affected the development of purkinje cell progenitors and differentiated cells.Interestingly,we found that the expression of wnt1 in cerebellum was decreased in Arl13 b mutants.Moreover,the cerebellar defects of Arl13 b mutants was partially rescued by treatment with lithium,an agonist of Wnt signaling pathway.Thus,our findings revealed the cellular and molecular mechanism of cerebellar development defects in Joubert syndrome caused by Arl13 b,which are provide basic data and expriments for probing the pathogenesis of cerebellar defects of Joubert syndrome and other cerebellum correlate diseases.Our study will provide a new approaches for monitoring and therapy of Joubert syndrome and other cerebellum pathologies.