High incidence of medulloblastoma following X-ray-irradiation of newborn Ptc1 heterozygous mice

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

doi:10.1038/sj.onc.1205973

Cited by 94 publications

(106 citation statements)

References 18 publications

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“…Downregulation of the expression of ErbB-4 cytoplasmic isoforms in Hh-dependent mouse MB To investigate the possible influence of Hh signalling on ErbB-4 expression during MB tumorigenesis, we used the Ptc1 þ /À mouse model, which reproduces MB caused by Hh pathway activation (Hahn et al, 1998;Pazzaglia et al, 2002). Reverse transcription-polymerase chain reaction (RT-PCR) analysis of 14 tumors confirmed the presence of active Hh signalling reflected by increased Gli1 expression and revealed significant downregulation of both the CYT-1 and CYT-2 isoforms of ErbB-4 ( Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets

Ferretti

Marcotullio

Gessi³

et al. 2006

Oncogene

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Medulloblastoma (MB) results from aberrant development of cerebellar neurons in which altered hedgehog (Hh) signalling plays a major role. We investigated the possible influence of Hh signalling on ErbB-receptor expression in MB, in particular that of the ErbB-4 CYT-1 and CYT-2 isoforms generated by alternative splicing of the cytoplasmic domain. ErbB-4 expression was downregulated in Hh-induced MBs from Patched-1 þ /À mice. Hh signalling (reflected by enhanced expression of the Gli1 transcription factor) inhibited ErbB-4 expression in mouse cerebellar granule progenitors and human MB cells. Analysis of 26 human primary MBs revealed a subset of 11 tumors characterized by low Gli1 levels, upregulated ErbB-4 expression and increased CYT-1:CYT-2 ratios. Interestingly, CYT-1 and Gli1 levels were inversely correlated. ErbB-4 CYT-1 and CYT-2 had different phenotypic effects in cultured MB cells: in response to neuregulin treatment, CYT-2 overexpression inhibited proliferation whereas CYT-1, which includes a phosphatidylinositol 3-kinase (PI3K)-binding site that is missing in CYT-2, enhanced resistance to starvation-and etoposide-induced apoptosis by activating PI3K/Akt signalling. CYT-1:CYT-2 ratios displayed correlation with tumor histotype and ErbB-2 levels, which are established prognostic indices for MB. These findings demonstrate that low-level Hh signalling in human MB is associated with the selective maintenance of high ErbB-4 CYT-1 expression, an alteration that exerts tumor-promoting effects.

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Section: Resultsmentioning

confidence: 99%

Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets

Ferretti

Marcotullio

Gessi³

et al. 2006

Oncogene

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“…(19,20) Both models were found to be prone to tumor development, skeletal abnormalities, and increased susceptibility to irradiation. (21)(22)(23) Because Hh-PTCH1 signaling plays a major role in osteoblast differentiation during endochondral bone formation and adult bone homeostasis, in addition to its role in increasing the predisposition to neoplasms, Ohba and colleagues examined bone metabolism in Ptch1 þ/-mice and found that these mice exhibit increased bone mass compared with their wild-type littermates. Moreover, Ptch1 þ/-mice additionally showed enhanced osteoclastogenesis and osteoblast differentiation.…”

Section: Introductionmentioning

confidence: 99%

Heterozygous PTCH1 Mutations Impact the Bone Metabolism in Patients With Nevoid Basal Cell Carcinoma Syndrome Likely by Regulating SPARC Expression

Hong

Zhang

et al. 2016

Journal of Bone and Mineral Research

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Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by bone and skin abnormalities and a predisposition to various tumors. Keratocystic odontogenic tumors (KCOTs), which are common tumors of the jaw that cause extensive damage to the jawbone, are usually accompanied with NBCCS. Germline PTCH1 mutations in NBCCS tumorigenesis have been frequently studied; however, little is known regarding the pathogenesis of bone abnormalities in this disease. This study sought to investigate the mechanism underlying heterozygous PTCH1 mutation-mediated abnormal bone metabolism in patients with NBCCS. Stromal cells were isolated from the fibrous capsules of patients with NBCCS-associated or non-syndromic keratocystic odontogenic tumors and non-syndromic tumor stromal cells without PTCH1 mutations served as controls. Germline PTCH1 heterozygous mutations were confirmed in all NBCCS samples and differential protein expression was identified using tandem mass tag-labeled proteomics analysis. Our findings revealed that osteonectin/SPARC expression was significantly downregulated in syndromic stromal cells compared with non-syndromic stromal cells. SPARC expression was even lower in stromal cells carrying PTCH1 protein truncation mutations. PTCH1 siRNA transfection demonstrated that SPARC downregulation correlates with decreased PTCH1 expression. Furthermore, exogenous SPARC promoted osteogenic differentiation of syndromic stromal cells with enhanced development of calcium nodules. In addition, bone mineral density tests showed that patients with NBCCS exhibit weak bone mass compared with sex-and age-matched controls. This study indicates that germline PTCH1 heterozygous mutations play a major role in bone metabolism in patients with NBCCS, in particular in those with PTCH1 protein truncation mutations. SPARC may represent an important downstream modulator of PTCH1 mediation of bone metabolism. Thus, bone mineral density monitoring is critical for patients with NBCCS for prevention of osteoporosis. In addition, surgical procedures on syndromic-associated KCOTs should be performed with consideration of the weaker bone mass in such patients.

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“…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

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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.

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High incidence of medulloblastoma following X-ray-irradiation of newborn Ptc1 heterozygous mice

Cited by 94 publications

References 18 publications

Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets

Alternative splicing of the ErbB-4 cytoplasmic domain and its regulation by hedgehog signaling identify distinct medulloblastoma subsets

Heterozygous PTCH1 Mutations Impact the Bone Metabolism in Patients With Nevoid Basal Cell Carcinoma Syndrome Likely by Regulating SPARC Expression

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

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