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Keywords:

  • Lyar;
  • p53;
  • neural tube;
  • synergistic lethality;
  • exencephaly

Abstract

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.