Original Paper

Synergistic regulation of p53 by Mdm2 and Mdm4 is critical in cardiac endocardial cushion morphogenesis during heart development†

  1. Qin Zhang1,2,
  2. Xueyan He1,
  3. Lai Chen1,
  4. Chenxi Zhang1,
  5. Xiang Gao1,
  6. Zhongzhou Yang1,
  7. Geng Liu1,*

Article first published online: 28 SEP 2012

DOI: 10.1002/path.4077

Issue

The Journal of Pathology

The Journal of Pathology

Volume 228, Issue 3, pages 416–428, November 2012

Additional Information

How to Cite

Zhang, Q., He, X., Chen, L., Zhang, C., Gao, X., Yang, Z. and Liu, G. (2012), Synergistic regulation of p53 by Mdm2 and Mdm4 is critical in cardiac endocardial cushion morphogenesis during heart development. J. Pathol., 228: 416–428. doi: 10.1002/path.4077

Author Information

  1. 1

    The MOE Key Laboratory of Model Animal for Disease Study and the Model Animal Research Center, Nanjing University, Nanjing, China

  2. 2

    Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

*Geng Liu, The MOE Key Laboratory of Model Animal for Disease Study and the Model Animal Research Center, Nanjing University, Nanjing, China e-mail: liugeng@nicemice.cn

  1. †

    No conflicts of interest were declared.

Publication History

  1. Issue published online: 12 OCT 2012
  2. Article first published online: 28 SEP 2012
  3. Accepted manuscript online: 20 JUL 2012 08:23AM EST
  4. Manuscript Accepted: 11 JUL 2012
  5. Manuscript Revised: 8 JUL 2012
  6. Manuscript Received: 15 FEB 2012

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Keywords:

  • p53;
  • congenital heart defects;
  • vasculogenesis;
  • endocardial cushion morphogenesis;
  • EMT

Abstract

Congenital heart defects (CHDs) are the most prevalent human birth defects. More than 85% of CHDs are thought to result from a combination of genetic susceptibilities and environmental stress. However, the stress-related signalling pathways involved remain largely unknown. The p53 transcription factor is a key tumour suppressor and a central regulator of the cellular stress responses. p53 activities are tightly regulated by its inhibitors Mdm2 and Mdm4 at the post-translational level. Here we used the Cre–loxP system to delete Mdm2 (Tie2Cre;Mdm2FM/FM) or one copy of both Mdm2 and Mdm4 (Tie2Cre;Mdm2FM/+; Mdm4+/−) in endothelial/endocardial cells and their derivatives in mice to examine the regulation of the p53/Mdm2–Mdm4 pathway during vascular and cardiovascular development. The Tie2Cre;Mdm2FM/FM mice died before embryonic day 10.5 (E10.5) and displayed severe vascular defects. On the other hand, the Tie2Cre;Mdm2FM/+; Mdm4+/− mice displayed atrial and ventricular septal defects (ASD, VSD) of the heart, leading to severe heart dysfunction and postnatal death. During cardiac endocardial cushion morphogenesis, p53 activation was associated with defects in both the epithelial-mesenchymal transition (EMT) of the endocardial cells and the post-EMT proliferation of the mesenchymal cells, and the valvuloseptal phenotypes of the Tie2Cre;Mdm2FM/+; Mdm4+/− mice were fully rescued by deletion of one copy of p53. Strikingly, maternal exposure to low-dose X-rays in C57BL/6 mice mimicked the congenital heart malformations seen in the Tie2Cre;Mdm2FM/+; Mdm4+/− model, which was also dependent on p53 status, establishing a link between maternal exposures and CHD susceptibility through the p53 pathway. These data revealed a new regulatory mechanism in cardiac endocardial cushion morphogenesis and suggested a possible cause of CHDs due to environmental stress. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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