PTEN Loss Collaborates With The Sonic Hedgehog Pathway In Medulloblastoma

Medulloblastoma is the most common malignant pediatric brain tumour.Many genes and signaling pathways have a significant impact on tumorigenesis.In the development of cerebellum,Sonic hedgehog(Shh)reased from the purkinje cells stimulates the proliferation of granular cells precursor(GNPs)in the external granule layer(EGL)by activating the Gli transcription factors.After a period of Shh-dependent proliferation,the granular cell precursor exit the cell cycle,migrate inwards and begin to differentiate.Finally,granule neurons past the Purkinje cell layer forming the internal granule layer(IGL)in the cerebellum.GNP cells are believed to be the origin of medulloblastoma.It is suggested that medulloblastoma arises from an aberration of normal cerebellum developmental process:overactivated Hh pathway express in EGL and the GNPs are over proliferation and fais to exit the cell cycle at the appropriate time and reside at the EGL.Recent publications find that PI3K-dependent signaling is frequently activated and PTEN gene expression is frequently silenced in medulloblatoma and loss of Pten in the context of heterozygosity for Ptcl accelerate medulloblastoma tumorigenesis,but little is known about the early stages of the disease.To investigate the role for cross talk between Pten loss and Sonic hedgehog signaling pathways in the early stage of medulloblastoma formation,we used an animal model of medulloblastoma in which mice are heterozygous for the Ptcl gene.We inactivate PTEN gene in neural stem cells(NSCs)and granular cells precursor(GNPs),which is achieved by using the Nestin-cre transgenic mice.In our study,almost all of the Ptenfl/+;Nes-cre;Ptc1+/-(Pten+/-;Ptc1+/-)transgenic mice have ectopic regions of ectopic cells in their cerebellum at 6 weeks of age.These ectopic cells may represent a pre-neoplastic stage of tumorigenesis.The ectopic cells are different from medulloblastomas in history.The protein level of Pten is downregulated and the PI3K/Akt(phosphrylated on serine 473)signaling is activated in part of the ectopic regions in the cerebellum of Ptenfl/+;Nes-cre;Ptc1+/-mice compared with Ptc1+/-mice at 6 weeks of age.In conclusion,our study provides a better understanding of the molecular signals in the early stages in medulloblastoma formation,and may yield new biology markers for the early detection of medulloblastoma.These and other findings may suggest an effective way to target this disease with activated PI3K signaling pathway.