Abstract
Medulloblastoma is the most common malignant pediatric brain tumor. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from this disease. Medulloblastoma includes four groups (SHH, WNT, Group 3 and Group 4), which show differences in karyotype, histology, and prognosis. Since some of these tumors originate from granule cell progenitors (GCPs) of the cerebellum a better understanding of the mechanisms controlling progenitor cycle exit and differentiation could unravel new promising targets for medulloblastoma. To gain insight into the mechanisms controlling GCP proliferation and differentiation, we performed RNA sequencing of GCPs at different stages of differentiation. These cells originate in the external germinal layer (EGL) of the cerebellum, undergo predominantly symmetric divisions during early postnatal EGL development, and exit the cell cycle within a narrow time frame. We studied GCP cell cycle exit and obtained several differentially expressed lncRNAs governing neuronal differentiation. We demonstrate that some of these lncRNAs are involved in GCP cell cycle exit and are potentially dysregulated in mouse models of medulloblastoma. Further, we demonstrate that the Anaphase Promoting Complex/cyclosome (APC/C) is also potentially dysregulated in medulloblastoma, thus leading to uncontrolled cell proliferation via lncRNA expression. These studies underscore a previously unappreciated role for APC/C in controlling epigenetic pathways in medulloblastoma.
