Abstract
The deubiquitinase HAUSP (herpesvirus-associated ubiquitin-specific protease; also called USP7) has a critical role in regulating the p53-Mdm2 (murine double minute 2) pathway. By using the conventional knockout approach, we previously showed that hausp inactivation leads to early embryonic lethality. To fully understand the physiological functions of hausp, we have generated mice lacking hausp specifically in the brain and examined the impacts of this manipulation on brain development. We found that deletion of hausp in neural cells resulted in neonatal lethality. The brains from these mice displayed hypoplasia and deficiencies in development, which were mainly caused by p53-mediated apoptosis. Detailed analysis also showed an increase of both p53 levels and p53-dependent transcriptional activation in hausp knockout brains. Notably, neural cell survival and brain development of hausp-mutant mice can largely be restored in the p53-null background. Nevertheless, in contrast to the case of mdm2- and mdm4 (murine double minute 4)-mutant mice, inactivation of p53 failed to completely rescue the neonatal lethality of these hausp-mutant mice. These results indicate that HAUSP-mediated p53 regulation is crucial for brain development, and also suggest that both the p53-dependent and the p53-independent functions of HAUSP contribute to the neonatal lethality of hausp-mutant mice.
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Abbreviations
- HAUSP:
-
herpesvirus-associated ubiquitin-specific protease
- Mdm2:
-
murine double minute 2
- Mdm4:
-
murine double minute 4
- nes-cre :
-
loxP site-specific recombinase gene cre driven by nestin promoter
- FL:
-
floxed allele
- p21:
-
cyclin-dependent kinase inhibitor 1
- BAX:
-
BCL2-associated X protein
- PUMA:
-
p53 upregulated modulator of apoptosis
- MEF:
-
mouse embryonic fibroblast
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Acknowledgements
We thank Dr. Neal Copeland for recombineering reagents; Qiong Li and Xi Sun for expert assistance with histology. This study was supported, in part, by grants from the NIH/NCI and by grants from the Leukemia and Lymphoma Society and Ellison Medical Foundation to WG.
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Kon, N., Zhong, J., Kobayashi, Y. et al. Roles of HAUSP-mediated p53 regulation in central nervous system development. Cell Death Differ 18, 1366–1375 (2011). https://doi.org/10.1038/cdd.2011.12
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DOI: https://doi.org/10.1038/cdd.2011.12
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