Mdm4 (Mdmx) Regulates p53-Induced Growth Arrest and Neuronal Cell Death during Early Embryonic Mouse Development

Abstract

We report here the characterization of a mutant mouse line with a specific gene trap event in the Mdm4 locus. Absence of Mdm4 expression results in embryonic lethality (10.5 days postcoitum [dpc]), which was rescued by transferring the Mdm4 mutation into a Trp53-null background. Mutant embryos were characterized by overall growth deficiency, anemia, improper neural tube closure, and dilation of lateral ventricles. In situ analysis demonstrated increased levels of p21^CIP1/Waf1 and lower levels of Cyclin E and proliferating cell nuclear antigen expression. Consistent with lack of 5-bromo-2′-deoxyuridine incorporation, these data suggest a block of mutant embryo cells in the G₁ phase of the cell cycle. Accordingly, Mdm4-deficient mouse embryonic fibroblasts manifested a greatly reduced proliferative capacity in culture. Moreover, extensive p53-dependent cell death was specifically detected in the developing central nervous system of the Mdm4 mutant embryos. These findings unambiguously assign a critical role for Mdm4 as a negative regulator of p53 and suggest that Mdm4 could contribute to neoplasias retaining wild-type Trp53. Finally, we provide evidence indicating that Mdm4 plays no role on cell proliferation or cell cycle control that is distinct from its ability to modulate p53 function.

Domenico Migliorini, Eros Lazzerini Denchi, and Davide Danovi contributed equally to this work.

We thank S. Minucci and M. Faretta for many helpful discussions and/or critically reviewing this manuscript.

This work was supported in part by grants from AIRC and EC. J.-C. Marine is a recipient of a fellowship from European Community (Marie Curie Fellowship). E.L.D. is a recipient of a fellowship from The FIRC Institute of Molecular Oncology.