Project description:Origins of the brain tumor, medulloblastoma, from stem cells or restricted pro-genitor cells are unclear. To investigate this, we activated oncogenic Hedgehog signaling in multipotent and lineage-restricted CNS progenitors. We observed that normal unipo-tent cerebellar granule neuron precursors (CGNP) derive from hGFAP+ and Olig2+ rhombic lip progenitors. Hedgehog activation in a spectrum of early and late stage CNS progenitors generated similar medulloblastomas, but not other brain cancers, indicating that acquisition of CGNP identity is essential for tumorigenesis. We show in human and mouse medulloblastoma that cells expressing the glia-associated markers Gfap and Olig2 are neoplastic and that they retain features of embryonic-type granule lineage progenitors. Thus, oncogenic Hedgehog signaling promotes medulloblastoma from lineage-restricted granule cell progenitors. Gene expression profiling of cerebellar tumors generated from various early and late stage CNS progenitor cells. Experiment Overall Design: Group comparisons with biological replicates
Project description:Origins of the brain tumor, medulloblastoma, from stem cells or restricted pro-genitor cells are unclear. To investigate this, we activated oncogenic Hedgehog signaling in multipotent and lineage-restricted CNS progenitors. We observed that normal unipo-tent cerebellar granule neuron precursors (CGNP) derive from hGFAP+ and Olig2+ rhombic lip progenitors. Hedgehog activation in a spectrum of early and late stage CNS progenitors generated similar medulloblastomas, but not other brain cancers, indicating that acquisition of CGNP identity is essential for tumorigenesis. We show in human and mouse medulloblastoma that cells expressing the glia-associated markers Gfap and Olig2 are neoplastic and that they retain features of embryonic-type granule lineage progenitors. Thus, oncogenic Hedgehog signaling promotes medulloblastoma from lineage-restricted granule cell progenitors. Gene expression profiling of cerebellar tumors generated from various early and late stage CNS progenitor cells.
Project description:Using a cytokeratin 5 gene promoter, we ectopically expressed a constitutively active zebrafish smoothened (smoa1) in presumably glial progenitor cells of zebrafish CNS. Stable transgenic zebrafish developed retinal tumors and low grade glioma of the optic nerve. Microarray analysis showed upregulation of Hh downstream targets of ptc1, gli1 and gli2a in tumors. Immunofluorescence studies confirmed overexpression of Pax2, GFAP, S100 and Sox2, specifically in gliomas. We also detected upregulated expression of phosphorylated pRb and Mdm2 associated with gliomagenesis. Our results suggest that dysregulated Hh signaling initiates tumorigenesis in zebrafish CNS. Zebrafish optic nerve maintains phosphorylated pRb expression, therefore provides a unique niche for pathogenesis of glioma. RNAs from 4 gross eye tumors (from fish of 4 months of age) and 4 normal eyes from wil-type control fish were extracted and used for array analysis