title: Aberrant activation of p53 due to loss of MDM2 or MDMX causes early lens dysmorphogenesis.
abstract: Although forming a heterodimer or heterooligomer is essential for MDM2 and MDMX to fully control p53 during early embryogenesis, deletion of either MDM2 or MDMX in specific tissues using the loxp-Cre system reveals phenotypic diversity during organ morphogenesis, which can be completely rescued by loss of p53, suggesting the spatiotemporal independence and specificity of the regulation of p53 by MDM2 and MDMX. In this study, we investigated the role of the MDM2-MDMX-p53 pathway in the developing lens that is a relatively independent region integrating cell proliferation, differentiation and apoptosis. Using the mice expressing Cre recombinase specifically in the lens epithelial cells (LECs) beginning at E9.5, we demonstrated that deletion of either MDM2 or MDMX induces apoptosis of LEC and reduces cell proliferation, resulting in lens developmental defect that finally progresses into aphakia. Specifically, the lens defect caused by MDM2 deletion was evident at E10, occurring earlier than that caused by MDMX deletion. These lens defects were completely rescued by loss of two alleles of p53, but not one allele of p53. These results demonstrate that both MDM2 and MDMX are required for monitoring p53 activity during lens development, and they may function independently or synergistically to control p53 and maintain normal lens morphogenesis.
authors.affiliation: Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Departments of Ophthalmology, Pathology & Cell Biology, Columbia University, 635 W. 165th Street, EI902A, New York, NY 10032, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA. Electronic address: hlu2@tulane.edu.
authors.forename: Hua
authors.initials: H
authors.lastname: Lu
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental; D006720:Homozygote; D007908:Lens, Crystalline / Q000002:abnormalities / Q000196:embryology*; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis; D010641:Phenotype; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Apoptosis; Cell proliferation; Eyes; Lens; Lens development; Lens dysmorphogenesis; MDM2; MDMX; p53