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Updated: Aug 8, 2026
A Non-random Mouse Model for Pharmacological Reactivation of Mecp2 on the Inactive X Chromosome
Published on: May 22, 2019
XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice
Catherine T Yan1, Dhruv Kaushal, Michael Murphy
1Howard Hughes Medical Institute, The Children's Hospital, CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115, USA.
Abstract:
Inactivation of the XRCC4 nonhomologous end-joining factor in the mouse germ line leads to embryonic lethality, in association with apoptosis of newly generated, postmitotic neurons. We now show that conditional inactivation of the XRCC4 in nestin-expressing neuronal progenitor cells, although leading to no obvious phenotype in a WT background, leads to early onset of neuronally differentiated medulloblastomas (MBs) in a p53-deficient background. A substantial proportion of the XRCC4/p53-deficient MBs have high-level N-myc gene amplification, often intrachromosomally in the context of complex translocations or other alterations of chromosome 12, on which N-myc resides, or extrachromosomally within double minutes. In addition, most XRCC4/p53-deficient MBs harbor clonal translocations of chromosome 13, which frequently involve chromosome 6 as a partner. One copy of the patched gene (Ptc), which lies on chromosome 13, was deleted in all tested XRCC4/p53-deficient MBs in the context of translocations or interstitial deletions. In addition, Cyclin D2, a chromosome 6 gene, was amplified in a subset of tumors. Notably, amplification of Myc-family or Cyclin D2 genes and deletion of Ptc also have been observed in human MBs. We therefore conclude that, in neuronal cells of mice, the nonhomologous end-joining pathway plays a critical role in suppressing genomic instability that, in a p53-deficient background, routinely contributes to genesis of MBs with recurrent chromosomal alterations.
Insights
The nonhomologous end-joining factor XRCC4 is crucial for preventing genomic instability in neuronal cells. Its inactivation, combined with p53 deficiency, promotes medulloblastoma development with specific chromosomal alterations.
Area of Science:
- Genetics
- Cancer Biology
- Neuroscience
Background:
- Inactivation of the XRCC4 nonhomologous end-joining factor in the mouse germ line causes embryonic lethality and neuronal apoptosis.
- The role of XRCC4 in neuronal progenitor cells and its impact on medulloblastoma development remained unclear.
Purpose of the Study:
- To investigate the role of XRCC4 in neuronal progenitor cells in the context of p53 deficiency.
- To identify genomic alterations associated with medulloblastoma development in XRCC4/p53-deficient mice.
Main Methods:
- Conditional inactivation of XRCC4 in nestin-expressing neuronal progenitor cells.
- Analysis of medulloblastomas in XRCC4/p53-deficient mice for genetic alterations.
- Comparison of genetic alterations with human medulloblastomas.
Main Results:
- Conditional XRCC4 inactivation in neuronal progenitors, coupled with p53 deficiency, led to early-onset medulloblastomas.
- XRCC4/p53-deficient medulloblastomas frequently exhibited N-myc amplification, chromosome 12 alterations, chromosome 13 translocations, and patched (Ptc) gene deletion.
- Amplification of Cyclin D2 and deletion of Ptc in mouse tumors mirrored alterations found in human medulloblastomas.
Conclusions:
- The nonhomologous end-joining pathway is critical for suppressing genomic instability in mouse neuronal cells.
- Genomic instability, exacerbated by p53 deficiency, drives medulloblastoma development with recurrent chromosomal alterations.
- XRCC4 plays a significant role in preventing medulloblastoma formation by maintaining genomic integrity.
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