title: Aberrant Otx2 expression enhances migration and induces ectopic proliferation of hindbrain neuronal progenitor cells.
abstract: Dysregulation of Otx2 is a hallmark of the pediatric brain tumor medulloblastoma, yet its functional significance in the establishment of these tumors is unknown. Here we have sought to determine the functional consequences of Otx2 overexpression in the mouse hindbrain to characterize its potential role in medulloblastoma tumorigenesis and identify the cell types responsive to this lineage-specific oncogene. Expression of Otx2 broadly in the mouse hindbrain resulted in the accumulation of proliferative clusters of cells in the cerebellar white matter and dorsal brainstem of postnatal mice. We found that brainstem ectopia were derived from neuronal progenitors of the rhombic lip and that cerebellar ectopia were derived from granule neuron precursors (GNPs) that had migrated inwards from the external granule layer (EGL). These hyperplasias exhibited various characteristics of medulloblastoma precursor cells identified in animal models of Shh or Wnt group tumors, including aberrant localization and altered spatiotemporal control of proliferation. However, ectopia induced by Otx2 differentiated and dispersed as the animals reached adulthood, indicating that factors restricting proliferative lifespan were a limiting factor to full transformation of these cells. These studies implicate a role for Otx2 in altering the dynamics of neuronal progenitor cell proliferation.
authors.affiliation: Department of Pathology, The Pediatric Brain Tumor Foundation Institute, and The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wortham
authors.forename: Genglin
authors.initials: G
authors.lastname: Jin
authors.forename: Julia Lailai
authors.initials: JL
authors.lastname: Sun
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Yiping
authors.initials: Y
authors.lastname: He
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000166:cytology*; D051857:Otx Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D012249:Rhombencephalon / Q000166:cytology*; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; C465570:Shh protein, mouse