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Molecular and Cellular Biology, August 2002, p. 5527-5538, Vol. 22, No. 15
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.15.5527-5538.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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

Domenico Migliorini,1 Eros Lazzerini Denchi,1,2 Davide Danovi,1 Aart Jochemsen,3 Manuela Capillo,2 Alberto Gobbi,2 Kristian Helin,1,2 Pier Giuseppe Pelicci,1,2* and Jean-Christophe Marine1*

Department of Experimental Oncology, European Institute of Oncology, 20141 Milan,1 The FIRC Institute of Molecular Oncology, 20139 Milan, Italy,2 Department of Molecular and Cell Biology and Center for Biomedical Genetics, Leiden University Medical Center, 2300 RA Leiden, The Netherlands3

Received 15 January 2002/ Returned for modification 15 February 2002/ Accepted 25 April 2002

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 p21CIP1/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.

* Corresponding author. Mailing address for Pier Giuseppe Pelicci: Department of Experimental Oncology, European Institute of Oncology, 435 Via Ripamonti, 20141 Milan, Italy. Phone: 39 0257489834. Fax: 39 0257489851. E-mail address for Pier Giuseppe Pelicci: pgpelicci{at}ieo.it.

* Corresponding author. Mailing address for Jean-Christophe Marine: Department of Experimental Oncology, European Institute of Oncology, 435 Via Ripamonti, 20141 Milan, Italy. Phone: 39 0257489834. Fax: 39 0257489851. E-mail address for Jean-Christophe Marine: cmarine{at}lar.ieo.it.

Molecular and Cellular Biology, August 2002, p. 5527-5538, Vol. 22, No. 15
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.15.5527-5538.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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