Linking DNA damage to medulloblastoma tumorigenesis in patched heterozygous knockout mice

Pazzaglia, Simonetta; Tanori, Mirella; Mancuso, Mariateresa; Rebessi, Simonetta; Leonardi, Simona; Majo, V. Di; Covelli, Vincenzo; Atkinson, Michael J.; Hahn, Heidi; Saran, Anna

doi:10.1038/sj.onc.1209032

Cited by 63 publications

(79 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although mouse studies are crucial for the analysis of cancer frequency, they are usually less informative for the dissection of end points, such as DSB processing and cell survival. The mouse cerebellum, however, is characterized by extended postnatal development, and the effects of inefficient HR or NHEJ on the processing of DNA damage can be detected and quantified in vivo (Pazzaglia et al, 2006b). Increasing evidence points to granule neuron precursors (GNPs) as the cells of origin of MB (Marino, 2005).…”

Section: Resultsmentioning

confidence: 99%

Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum

et al. 2011

Self Cite

View full text Add to dashboard Cite

Heterozygous Patched1 (Ptc1 þ /À ) mice are prone to medulloblastoma (MB), and exposure of newborn mice to ionizing radiation dramatically increases the frequency and shortens the latency of MB. In Ptc1 þ /À mice, MB is characterized by loss of the normal remaining Ptc1 allele, suggesting that genome rearrangements may be key events in MB development. Recent evidence indicates that brain tumors may be linked to defects in DNA-damage repair processes, as various combinations of targeted deletions in genes controlling cell-cycle checkpoints, apoptosis and DNA repair result in MB in mice. Non-homologous end joining (NHEJ) and homologous recombination (HR) contribute to genome stability, and deficiencies in either pathway predispose to genome rearrangements. To test the role of defective HR or NHEJ in tumorigenesis, control and irradiated Ptc1 þ / À mice with two, one or no functional Rad54 or DNA-protein kinase catalytic subunit (DNA-PKcs) alleles were monitored for MB development. We also examined the effect of Rad54 or DNA-PKcs deletion on the processing of endogenous and radiation-induced double-strand breaks (DSBs) in neural precursors of the developing cerebellum, the cells of origin of MB. We found that, although HR and NHEJ collaborate in protecting cells from DNA damage and apoptosis, they have opposite roles in MB tumorigenesis. In fact, although Rad54 deficiency increased both spontaneous and radiation-induced MB development, DNA-PKcs disruption suppressed MB tumorigenesis. Together, our data provide the first evidence that Rad54-mediated HR in vivo is important for suppressing tumorigenesis by maintaining genomic stability.

show abstract

Section: Resultsmentioning

confidence: 99%

Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum

et al. 2011

Self Cite

View full text Add to dashboard Cite

show abstract

“…Mice in which a copy of the Ptc1 gene has been knocked out (Ptc1 1/2 ) are developmentally nearly normal in a large number of instances but show a marked predisposition to tumor development, including MB [18,19]. Our previous work has shown that irradiation of Ptc1 1/2 mice during postnatal days 1-4, when granule PCs are highly proliferative, dramatically increases the frequency of MB [20,21]. Here, we investigate the mechanisms through which multipotent NCSs and fate-restricted PCs respond to DNA damage induced by radiation, the effect of radiation exposure on cerebellar patterning and their likelihood of oncogenic transformation.…”

Section: Introductionmentioning

confidence: 99%

Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum

et al. 2013

View full text Add to dashboard Cite

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 1/2 ) provide a powerful model of medulloblastoma (MB), a frequent pediatric tumor of the cerebellum. Irradiation of newborn Ptc1 1/2 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 faterestricted 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.

show abstract

“…As we described previously (Pazzaglia, 2006;Pazzaglia et al, 2006), abnormal cerebellar regions with morphology varying from focal subpial aggregates of CGNPs to overt nodules are evident by histological examination of cerebella from asymptomatic Ptc1 mutants. We show here that the frequency of these lesions is strongly influenced by mouse age (Figure 2).…”

mentioning

confidence: 97%

Two-hit model for progression of medulloblastoma preneoplasia in Patched heterozygous mice

et al. 2006

Self Cite

View full text Add to dashboard Cite

Inactivation of one Ptc1 allele predisposes humans and mice to spontaneous medulloblastoma development, and irradiation of newborn Ptc1 heterozygous mice results in dramatic increase of medulloblastoma incidence. While a role for loss of wild-type (wt) Ptc1 (LOH) in radiationinduced medulloblastomas from Ptc1 neo67/ þ mice is well established, the importance of this event in spontaneous medulloblastomas is still unclear. Here, we demonstrate that biallelic Ptc1 loss plays a crucial role in spontaneous medulloblastomas, as shown by high rate of wt Ptc1 loss in spontaneous tumors. In addition, remarkable differences in chromosomal events involving the Ptc1 locus in spontaneous and radiation-induced medulloblastomas suggest distinct mechanisms for Ptc1 loss. To assess when, during tumorigenesis, Ptc1 loss occurs, we characterized cerebellar abnormalities that precede tumor appearance in Ptc1 neo67/ þ mice. We show that inactivation of only one copy of Ptc1 is sufficient to give rise to abnormal cerebellar proliferations with different degree of altered cell morphology, but lacking potential to progress to neoplasia. Furthermore, we identify biallelic Ptc1 loss as the event causally related to the transition from the preneoplastic stage to full blown medulloblastoma. These results underscore the utility of the Ptc1 neo67/ þ mouse model for studies on the mechanisms of medulloblastoma and for development of new therapeutic strategies.

show abstract

Linking DNA damage to medulloblastoma tumorigenesis in patched heterozygous knockout mice

Cited by 63 publications

References 38 publications

Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum

Opposite modifying effects of HR and NHEJ deficiency on cancer risk in Ptc1 heterozygous mouse cerebellum

Developmental and oncogenic radiation effects on neural stem cells and their differentiating progeny in mouse cerebellum

Two-hit model for progression of medulloblastoma preneoplasia in Patched heterozygous mice

Contact Info

Product

Resources

About