title: Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum.
abstract: Neural stem cells are highly susceptible to radiogenic DNA damage, however, little is known about their mechanisms of DNA damage response (DDR) and the long-term consequences of genotoxic exposure. Patched1 heterozygous mice (Ptc1(+/-)) provide a powerful model of medulloblastoma (MB), a frequent pediatric tumor of the cerebellum. Irradiation of newborn Ptc1(+/-) mice dramatically increases the frequency and shortens the latency of MB. In this model, we investigated the mechanisms through which multipotent neural progenitors (NSCs) and fate-restricted progenitor cells (PCs) of the cerebellum respond to DNA damage induced by radiation, and the long-term developmental and oncogenic consequences. These responses were assessed in mice exposed to low (0.25 Gy) or high (3 Gy) radiation doses at embryonic day 13.5 (E13.5), when NSCs giving rise to the cerebellum are specified but the external granule layer (EGL) has not yet formed, or at E16.5, during the expansion of granule PCs to form the EGL. We found crucial differences in DDR and apoptosis between NSCs and fate-restricted PCs, including lack of p21 expression in NSCs. NSCs also appear to be resistant to oncogenesis from low-dose radiation exposure but more vulnerable at higher doses. In addition, the pathway to DNA repair and the pattern of oncogenic alterations were strongly dependent on age at exposure, highlighting a differentiation-stage specificity of DNA repair pathways in NSCs and PCs. These findings shed light on the mechanisms used by NSCs and PCs to maintain genome integrity during neurogenesis and may have important implications for radiation risk assessment and for development of targeted therapies against brain tumors.
authors.affiliation: Laboratory of Radiation Biology and Biomedicine, Agenzia Nazionale per le Nuove Tecnologie, l'Energia e lo Sviluppo Economico Sostenibile (ENEA), CR-Casaccia, Rome, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Tanori
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pasquali
authors.forename: Simona
authors.initials: S
authors.lastname: Leonardi
authors.forename: Arianna
authors.initials: A
authors.lastname: Casciati
authors.forename: Paola
authors.initials: P
authors.lastname: Giardullo
authors.forename: Ilaria
authors.initials: I
authors.lastname: De Stefano
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Mancuso
authors.forename: Anna
authors.initials: A
authors.lastname: Saran
authors.forename: Simonetta
authors.initials: S
authors.lastname: Pazzaglia
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D002454:Cell Differentiation / Q000502:physiology / Q000528:radiation effects; D002531:Cerebellum / Q000166:cytology / Q000254:growth & development* / Q000473:pathology / Q000528:radiation effects*; D004249:DNA Damage; D004260:DNA Repair; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000166:cytology / Q000502:physiology / Q000528:radiation effects*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology* / Q000528:radiation effects*
keywords: Apoptosis; Carcinogenesis; DNA repair; Medulloblastoma; Neural stem cells; Progenitor cells; Ptc1+/− mice; p21