title: Mutations in Lyar and p53 are synergistically lethal in female mice.
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 Lyar(gt) 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. Lyar(gt/gt) mice were crossed to mice lacking the p53 tumor suppressor protein and Lyar/p53 compound mutants scored for external abnormalities.
  
  
  RESULTS
  Lyar(gt/gt) homozygotes are viable, fertile, and indistinguishable from wild type littermates. However, the growth of Lyar(+/gt) and Lyar(gt/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 Lyar(gt/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 Lyar(gt/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.
authors: Department of Basic Medical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, Indiana 47907, USA.
authors: Guan
authors: G
authors: Wang
authors: Christopher M
authors: CM
authors: Fulkerson
authors: Reem
authors: R
authors: Malek
authors: Sara
authors: S
authors: Ghassemifar
authors: Paul W
authors: PW
authors: Snyder
authors: Susan M
authors: SM
authors: Mendrysa
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D018703:Founder Effect; D005838:Genotype; D006720:Homozygote; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D009154:Mutation; D009436:Neural Tube Defects / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D012737:Sex Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C081182:Lyar protein, mouse; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53