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The patched (Ptc1) protein is a negative regulator of sonic hedgehog signaling, a genetic pathway whose perturbation causes developmental defects and predisposition to specific malignant tumors. Humans and mice with mutated Ptc1 are prone to medulloblastoma and basal cell carcinoma (BCC), both tumors showing dependence on radiation damage for rapid onset and high penetrance. Poly(ADP-ribose) polymerase (PARP-1) is a nuclear enzyme that plays a multifunctional role in DNA damage signaling and repair. In healthy and fertile PARP-1-null mice, radiation exposure reveals an extreme sensitivity and a high genomic instability. To test for interactions between PARP-1 and sonic hedgehog signaling, PARP-1-null mice were crossed to Ptc1 heterozygous mice. PARP-1 deletion further accelerated medulloblastoma development in irradiated Ptc1(+/-) mice, showing that PARP-1 inactivation sensitizes cerebellar cells to radiation tumorigenic effects. In addition to increased formation and slowed down kinetics of disappearance of gamma-H2AX foci, we observed increased apoptosis in PARP-1-deficient granule cell progenitors after irradiation. Double-mutant mice were also strikingly more susceptible to BCC, with >50% of animals developing multiple, large, infiltrative tumors within 30 weeks of age. The results provide genetic evidence that PARP-1 function suppresses sonic hedgehog pathway-associated tumors arising in response to environmental stress.

Individuals affected with the Gorlin syndrome inherit a germ-line mutation of the patched (Ptc1) developmental gene and, analogously to Ptc1 heterozygous mice, show an increased susceptibility to spontaneous tumor development. Human and mouse Ptc1 heterozygotes (Ptc1(+/-)) are also hypersensitive to ionizing radiation (IR)-induced tumorigenesis in terms of basal cell carcinoma (BCC) induction. We have analysed the involvement of Ptc1 in the tumorigenic response to a single dose of 3 Gy X-rays in neonatal and adult Ptc1 heterozygous and wild type mice. We report that irradiation dramatically increased the incidence of medulloblastoma development (51%) over the spontaneous rate (7%) in neonatal but not adult Ptc1 heterozygotes, indicating that medulloblastoma induction by IR is subjected to temporal restriction. Analysis of Ptc1 allele status in the tumors revealed loss of the wild type allele in 17 of 18 medulloblastomas from irradiated mice and in two of three spontaneous medulloblastomas. To our knowledge, irradiated newborn Ptc1(+/-) heterozygous mice constitute the first mouse model of IR-induced medulloblastoma tumorigenesis, providing a useful tool to elucidate the molecular basis of medulloblastoma development.