This article is a US Government work and, as such, is in the public domain in the United States of America.
Article first published online: 19 JUL 2012
Published 2012 Wiley Periodicals, Inc.
Birth Defects Research Part A: Clinical and Molecular Teratology
Volume 94, Issue 9, pages 729–737, September 2012
How to Cite
Wang, G., Fulkerson, C. M., Malek, R., Ghassemifar, S., Snyder, P. W. and Mendrysa, S. M. (2012), Mutations in Lyar and p53 are synergistically lethal in female mice. Birth Defects Research Part A: Clinical and Molecular Teratology, 94: 729–737. doi: 10.1002/bdra.23048
Supported in part by a grant from the Purdue Research Foundation (to S.M.M.).
- Issue published online: 7 SEP 2012
- Article first published online: 19 JUL 2012
- Manuscript Accepted: 31 MAY 2012
- Manuscript Revised: 30 MAY 2012
- Manuscript Received: 24 MAR 2012
- neural tube;
- synergistic lethality;
Ly-1 antibody reactive clone (LYAR) is a nucleolar zinc finger protein that has been implicated in cell growth, self-renewal of embryonic stem cells, and medulloblastoma. To test whether LYAR is critical for cell growth and development, we generated Lyar mutant mice.
Mice carrying the mutant Lyargt allele were generated from embryonic stem cells that contained a gene-trap insertion in the Lyar gene. Phenotypic analyses were performed on Lyar mutant mice and mouse embryonic fibroblasts. Lyargt/gt mice were crossed to mice lacking the p53 tumor suppressor protein and Lyar/p53 compound mutants scored for external abnormalities.
Lyargt/gt homozygotes are viable, fertile, and indistinguishable from wild type littermates. However, the growth of Lyar+/gt and Lyargt/gt mouse embryonic fibroblasts (MEFs) was impaired, coincident with an increase in the steady-state level of p53 and a key p53 effector of growth arrest, p21, suggesting that a cellular stress response is triggered in the absence of a wild type level of LYAR. Remarkably, the majority of Lyar+/gt and Lyargt/gt female mice lacking p53 mice failed to survive. The neural tube defect (NTD) exencephaly was observed in ≈26% and ≈61% of female Lyar+/gt;p53−/− and Lyargt/gt;p53−/− embryos, respectively.
Lyar/p53 mutant mice represent a new digenic model of NTDs. Furthermore, these studies identify Lyar as a novel candidate gene for a role in human NTDs. These results provide new data to support the idea that loss of a p53-mediated developmental checkpoint may increase the risk of NTDs owing to some germline mutations. © Birth Defects Research (Part A) 94:729–737, 2012. Published 2012 Wiley Periodicals, Inc.