title: p53 pathway is involved in cell competition during mouse embryogenesis.
abstract: The function of tumor suppressor p53 has been under intense investigation. Acute stresses such as DNA damage are able to trigger a high level of p53 activity, leading to cell cycle arrest or apoptosis. In contrast, the cellular response of mild p53 activity induced by low-level stress in vivo remains largely unexplored. Murine double minute (MDM)2 and MDM4 are two major negative regulators of p53. Here, we used the strategy of haploinsufficiency of Mdm2 and Mdm4 to induce mild p53 activation in vivo and found that Mdm2+/-Mdm4+/-double-heterozygous mice exhibited normal embryogenesis. However, closer examination demonstrated that the Mdm2+/-Mdm4+/-cells exhibited a growth disadvantage and were outcompeted during development in genetic mosaic embryos that contained wild-type cells. Further study indicated the out-competition phenotype was dependent on the levels of p53. These observations revealed that cells with mild p53 activation were less fit and exhibited altered fates in a heterotypic environment, resembling the cell competition phenomenon first uncovered in Drosophila By marking unfit cells for elimination, p53 may exert its physiological role to ensure organ and animal fitness.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, JiangSu 210061, China.|Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, JiangSu 210061, China.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, JiangSu 210061, China.|Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, JiangSu 210061, China.
authors.forename: Yinyin
authors.initials: Y
authors.lastname: Xie
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, JiangSu 210061, China.|Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, JiangSu 210061, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, JiangSu 210061, China.|Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, JiangSu 210061, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Xiang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, JiangSu 210061, China.|Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, JiangSu 210061, China.|Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330004, China.
authors.forename: Lai
authors.initials: L
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, JiangSu 210061, China.|Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, JiangSu 210061, China.
authors.forename: Chenxi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, JiangSu 210061, China.|Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, JiangSu 210061, China.
authors.forename: Xiaoshuang
authors.initials: X
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, JiangSu 210061, China.|Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, JiangSu 210061, China.
authors.forename: Jiong
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908.
authors.forename: Hui
authors.initials: H
authors.lastname: Zong
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, JiangSu 210061, China; liug53@nju.edu.cn.|Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, JiangSu 210061, China.
authors.forename: Geng
authors.initials: G
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology*; D005260:Female; D057895:Haploinsufficiency; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009030:Mosaicism; D010179:Pancreas / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D010641:Phenotype; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C461497:Mdm4 protein, mouse; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2
keywords: cell competition; embryogenesis; p53; stress response; tissue fitness