Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice
| Autor: | Ondrea Graves, John Y.H. Kim, Aaron L Nelson, Lisa Marie Sturla, Liliana Goumnerova, David H. Rowitch, Scott L. Pomeroy, Sibel A Algon, Rosalind A. Segal |
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| Rok vydání: | 2003 |
| Předmět: |
Patched Receptors
Patched Heterozygote Cerebellum Mouse endocrine system diseases Cellular differentiation Apoptosis Receptors Cell Surface Biology Mice patched Proliferation Granule cell medicine Animals Humans Cell Lineage Receptor trkC Sonic hedgehog Cerebellar Neoplasms Molecular Biology Genetics Stem Cells Intracellular Signaling Peptides and Proteins Gene Expression Regulation Developmental Membrane Proteins Cell Differentiation Cell Biology Cerebellar granule cell differentiation Patched-1 Receptor Phenotype medicine.anatomical_structure CXCL3 trkC Cancer research biology.protein Cell Division Medulloblastoma Developmental Biology |
| Zdroj: | Developmental Biology. 263:50-66 |
| ISSN: | 0012-1606 |
| DOI: | 10.1016/s0012-1606(03)00434-2 |
| Popis: | Medulloblastoma is a cerebellar tumor that can arise through aberrant activation of Sonic hedgehog (Shh) signaling, which normally regulates cerebellar granule cell proliferation. Mutations of the Shh receptor PATCHED (PTCH) are associated with medulloblastomas, which have not been found to have loss of PTCH heterozygosity. We address whether patched (Ptc) heterozygosity fundamentally alters granule cell differentiation and contributes to tumorigenesis by increasing proliferation and/or decreasing apoptosis in Ptc+/− mice. Our data show that postnatal Ptc+/− mouse granule cell precursor growth is not globally altered. However, many older Ptc+/− mice display abnormal cerebellar regions containing persistently proliferating granule cell precursors. Since fewer Ptc+/− mice form medulloblastomas, these granule cell rests represent a developmentally disrupted, but uncommitted stage of tumorigenesis. Although Ptc+/− mouse medulloblastomas express neurodevelopmental genes, they diverge from granule cell differentiation in their discordant coexpression of postmitotic markers despite their ongoing growth. Like human medulloblastomas, mouse tumors with reduced levels of the neurotrophin-3 receptor, trkC/Ntrk3, display decreased apoptosis in vivo, illustrating the role of TrkC in regulating tumor cell survival. These results indicate that Ptc heterozygosity contributes to tumorigenesis by predisposing a subset of granule cell precursors to the formation of proliferative rests and subsequent dysregulation of developmental gene expression. |
| Databáze: | OpenAIRE |
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