The Role Of Transcription Factor Stox1 In Cerebellar Development And Medulloblastoma Growth

Background: The cerebellum is an important ogan of the central nervous system(CNS),which is associated with motor coordination,cognitive processing and sensory discrimination.Medulloblastoma(MB),the most common type of childhood nervous system tumors,are proposed to arise from defects in cerebellar development.In early postnatal stage,SHH signaling pathway drives a rapid expansion of granule neural progenitors(GNPs).Math1,a transcription factor specifically expressed in the proliferating GNPs,is a key factor in cerebellar development and is a commonly used cerebellar external granule layer(EGL)marker.Storkhead box 1(Stox1),closely related to the forkhead transcription factor family,is abundant in the CNS and is associated with Alzheimer's disease.Objects: Signaling pathways and key molecules that act to control normal cerebellar neurogenesis and MB oncogenesis remain poorly identified.We performed this research to dicipher the role and machnisms of Stox1 in cerebellar development and medulloblastoma progression.Methods :(1)The expression pattern of Stox1 in developing cerebellum and spontaneous tumors of Ptch+/-mice was determined by quantitative RT-PCR and Immunobloting.(2)GNPs,purified by a percoll gradient sedimentation method,were infected with Stox1 overexpression or knockdown adenovirus.We performed quantitative RT-PCR,immunofluorescent staining and EdU assay to explore the role of Stox1 in differentiation and proliferation of GNPs.(3)We further explored the transcriptional regulation of Stox1 on Math1 by Math1 enhancer reporter assays and ChIP experiments.(4)The impact of Stox1 on medulloblatoma growth was analyzed by in vivo xenograft tumor implantation experiments.Results:(1)Stox1 was expressed in granule neurons of EGL in postnatal developing cerebellum.(2)Stox1 promoted the differentiation of cerebellar granule progenitor cells(3)Stox1 served as a transcriptional suppressor of Math1 and was modulated by SHH signaling.(4)Stox1 overexpression inhibited the Ptch+/-tumor growth in vivo.Conclusions:Expression of Stox1 is upregulated along with GNP differentiation and repressed by activation of Sonic Hedgehog(SHH)signaling.Stox1 plays a pivotal role in cerebellar granule differentiation and MB suppression.Stox1 exerts its neurogenic and oncosuppressing effect via direct transcriptional repression of Math1.In conclusion,this study illustrates a SHH-Stox1-Math1 regulatory axis in normal cerebellar development and MB formation.