Sonic Hedgehog-Dependent Growth Of Granule Cell Precursors Is Required For Cerebellar Development

Genetic studies of the signaling pathways believed that some evolutionary conserved signaling pathways,including bone morphogenetic protein BMP signaling pathway,Wnt signaling pathway,Notch and Hedgehog(Hh)signaling pathways involved in the development of almost all animals.Although cell growth environment determined the final output of a signal pathway,most of the experimental studies have shown that most of the signal pathway ligands,receptors,membrane signal transduction and transcription factors are evolutionarily conserved.Hedgehog(Hh)signaling pathway plays an important role in the regulation of growth and differentiation of a cell,embryonic development and tumor initiation shaping growth,and evolutionarily conserved from invertebrates to vertebrates.In vertebrates,depending on the Hh protein,Hh signaling pathway can be divided into three types: Sonic Hedgehog(Shh)?Desert Hedgehog(Dhh)and Indian Hedgehog(Ihh).Their Regulation range and distribution are different.Shh signaling pathway which is the study of the most mature,but also more widely distributed in the body.A number of studies show that Shh signaling pathway plays a crucial role in the early development in mammals for the maintenance of the neural tube development.In the form of the brain during development,growth and the formation of the cerebellum is a unique structure area.In the course of development of the neonate cerebellum,cerebellum will be dramatic increase in volume initially.This volume increasing mainly depends on the rapid proliferation and expansion of granule cells.granule cells are the most abundant neuronal population of the cerebellum.The cortex of the mature cerebellum consists of several well-defined neuronal cell populations that are positioned in distinct layers due to the precise coordination of cell proliferation,differentiation,and migration events that occur during development.During development of the cerebellum,there are two distinct proliferative zones: the ventricular neuroepithelium and the external granule layer(egl).EGL is a granule cell precursor cells(GCPs)composition.Postnatal mice,Granule cell precursor cells continued proliferation and expansion,until about two weeks after birth.After that,granule cell precursor cells mitosis to form particles of neurons,and migrated to the bottom of EGL layer formed the internal granule layer(IGL).IGL is composed by primarily of granule cell neurons.This radial migration of post-mitotic granule neurons is thought to be depended on Bergmann glia.The power of granule cell precursor cells proliferation and differentiation comes from Purkinje cells.Purkinje cells could extend their dendrites to the egl and begin to form a monolayer called Purkinje cell layer(PCL).Purkinje cells can produce and secrete SHH.As a proliferation factor,SHH binds to an inhibitory receptor PTCH which located EGL granule cell precursor cells on.PTCH for SHH signaling pathway downstream of the activated receptor Smo inhibition lifted.It leads to SHH signaling pathway activation and stimulates cell self-renewal,in order to maintain the EGL amplification.Medulloblastoma(MB)is the most common and a high degree of malignancy of brain cancer in children.It originated in the cerebellar granule cell layer of immature granule neuronal precursor cells or neural stem cells in the deep.Numerous studies indicate that abnormal activation of SHH signaling pathway has a very close relationship with the incidence of medulloblastoma.One hypothesis of the formation of MB is PTCH gene mutation.This mutation leads to SHH signaling pathway overactivation and EGL over amplified,resulting in cancer.The latest research shows that deletion of Ptch gene will lead to medulloblastoma spontaneously of mices about seven months after birth.And In the six weeks,the surface of the cerebellum in mice will be a lot of ectopic cells.These ectopic cells is Very similar to tumor cells on pathological.However,the molecular mechanisms occurring MB is still unclear.Our study found that SHH signaling is important signal in early cerebellar development.We observed that the migration process of granule cells through establishment brain slice culture system in vitro.Once SHH signal is blocked,the external granular layer cells significantly inhibited proliferation,but migration is almost unaffected.Ptch gene deletion leads to EGL cells abnormal migration to IGL.We hope through the observation of the early development of the cerebellum to find the affection of SHH signaling pathway to the early development of the cerebellum,suggesting that the molecular mechanisms occurring MB.