TY - JOUR T1 - Nos2 Inactivation Promotes the Development of Medulloblastoma in Ptch1+/− Mice by Deregulation of Gap43–Dependent Granule Cell Precursor Migration A1 - Haag, Daniel A1 - Zipper, Petra A1 - Westrich, Viola A1 - Karra, Daniela A1 - Pfleger, Karin A1 - Toedt, Grischa A1 - Blond, Frederik A1 - Delhomme, Nicolas A1 - Hahn, Meinhard A1 - Reifenberger, Julia A1 - Reifenberger, Guido A1 - Lichter, Peter Y1 - 2012/03/15 N2 - Author Summary Medulloblastoma is a common pediatric brain tumor, a subtype of which is driven by aberrant hedgehog pathway activation in cerebellar granule cell precursors. Although this tumor etiology has been intensively investigated in the well-established Ptch1+/− mouse model, knowledge is still lacking about the molecular interactions between neoplastic transformation and other developmental processes. Nitric oxide (NO) has been reported to be involved in controlling proliferation and differentiation of these cells. Therefore, inactivation of the NO–producing enzyme Nos2 in combination with the mutated Ptch1 gene should provide insight into how developmental regulation influences pathogenesis. Here, we describe a new role for NO in developing neuronal precursors of the cerebellum facilitating physiologically accurate migration via regulation of Gap43. We further demonstrate that disturbance of these processes leads to retention of granule precursor cells to the cerebellar periphery. Together with the sustained proliferation of these cells in combined Ptch1+/− Nos2−/− mice, this effect results in an increased medulloblastoma incidence relative to Ptch1+/− mice and demonstrates a new disease-promoting mechanism in this tumor entity. JF - PLOS Genetics JA - PLOS Genetics VL - 8 IS - 3 UR - https://doi.org/10.1371/journal.pgen.1002572 SP - e1002572 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pgen.1002572 ER -