1. ¹Biotechnology Unit, ENEA CR-Casaccia, Rome, Italy
2. ²Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy
3. ³Radiation Protection Unit, ENEA CR-Casaccia, Rome, Italy
4. ⁴Institute of Pathology, GSF National Research Center, Germany
5. ⁵Institute of Human Genetics, University of Goettingen, Germany

Correspondence: Dr S Pazzaglia, Biotechnology Unit, ENEA, Via Anguillarese 301, CR Casaccia, 00060 Rome, Italy. E-mail: pazzaglia@casaccia.enea.it

Received 7 April 2005; Revised 1 July 2005; Accepted 25 July 2005; Published online 9 January 2006.

Abstract

Hemizygous Ptc1 mice have many features of Gorlin syndrome, including predisposition to medulloblastoma development. Ionizing radiation synergize with Ptc1 mutation to induce medulloblastoma only in neonatally exposed mice. To explore the mechanisms underlying age-dependent susceptibility, we irradiated Ptc^neo67/+ mice at postnatal day 1 (P1) or 10 (P10). We observed a dramatic difference in medulloblastoma incidence, which ranged from 81% in the cerebellum irradiated at P1 to 3% in the cerebellum irradiated at P10. A stricking difference was also detected in the frequency of cerebellar preneoplastic lesions (100 versus 14%). Our data also show significantly lower induction of apoptosis in the cerebellum of medulloblastoma-susceptible (P1) compared to -resistant (P10) mice, strongly suggesting that medulloblastoma formation in Ptc1 mutants may be associated with resistance to radiation-induced cell killing. Furthermore, in marked contrast with P10 mice, cerebellum at P1 displays substantially increased activation of the cell survival-promoting Akt/Pkb protein, and markedly decreased p53 levels in response to radiation-induced genotoxic stress. Overall, these results show that developing cerebellar granule neuron precursors' (CGNPs) radiosensitivity to radiation-induced cell death increases with progressing development and inversely correlates with their ability to neoplastically transform.