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Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome
H Hahn1, L Wojnowski, A M Zimmer
1Section on Genetics, National Institute of Mental Health, Bethesda, MD 20892, USA.
Abstract:
Gorlin (or nevoid basal cell carcinoma) syndrome is characterized by a variety of clinical problems including generalized overgrowth of the body, cysts, developmental abnormalities of the skeleton and a predisposition to benign and malignant tumors. The syndrome results from germline mutations of the human homolog of the drosophila segment polarity gene patched (ptc). Here we report that mice heterozygous for ptc develop many of the features characteristic of Gorlin syndrome and that they exhibit a high incidence of rhabdomyosarcomas (RMS), the most common soft-tissue sarcoma in children. The downstream signalling partner of ptc, gli1, was overexpressed in all RMSs analyzed, indicating that abnormal signalling of the ptc-gli1 pathway may be common for the various tumors associated with the syndrome. igf2, implicated in the formation of RMSs, was also overexpressed, suggesting cross-talk between the ptc and igf2 pathways in tumorigenesis. Developmental defects in Gorlin syndrome resemble those induced by ionizing radiation. We show that ptc heterozygous mice exhibit increased incidence of radiation-induced teratogenesis. This suggests a role for ptc in the response to ionizing radiation and provides a model for both the systemic (developmental) and stochastic (cancer) abnormalities observed in Gorlin syndrome.
Insights
Mice with mutations in the patched (ptc) gene mimic Gorlin syndrome, developing tumors like rhabdomyosarcomas and showing increased radiation sensitivity. This highlights ptc
Area of Science:
- Genetics
- Developmental Biology
- Oncology
Background:
- Gorlin syndrome involves developmental abnormalities and tumor predisposition, caused by mutations in the patched (ptc) gene.
- The ptc gene is a homolog of a Drosophila segment polarity gene, crucial in developmental pathways.
Purpose of the Study:
- To investigate the role of the ptc gene in Gorlin syndrome pathogenesis using a mouse model.
- To explore the molecular mechanisms underlying tumor development and developmental defects in Gorlin syndrome.
Main Methods:
- Generation and analysis of mice heterozygous for the ptc gene.
- Molecular analysis of tumor tissues, including gene expression profiling (gli1, igf2).
- Assessment of radiation-induced teratogenesis in ptc heterozygous mice.
Main Results:
- Mice heterozygous for ptc exhibit features of Gorlin syndrome, including developmental abnormalities and a high incidence of rhabdomyosarcomas (RMS).
- Overexpression of gli1 and igf2 was observed in RMSs, suggesting aberrant ptc-gli1 and ptc-igf2 pathway signaling in tumorigenesis.
- ptc heterozygous mice showed increased susceptibility to radiation-induced teratogenesis.
Conclusions:
- The ptc gene plays a significant role in Gorlin syndrome, influencing both developmental processes and cancer susceptibility.
- Aberrant signaling through the ptc-gli1 pathway is implicated in the diverse tumors associated with the syndrome.
- ptc heterozygous mice provide a valuable model for studying Gorlin syndrome and its associated developmental and carcinogenic abnormalities, including radiation response.
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