Targeted inactivation of p12, CDK2 associating protein 1, leads to early embryonic lethality

PLoS One. 2009;4(2):e4518. doi: 10.1371/journal.pone.0004518. Epub 2009 Feb 20.


Targeted disruption of murine Cdk2ap1, an inhibitor of CDK2 function and hence G1/S transition, results in the embryonic lethality with a high penetration rate. Detailed timed pregnancy analysis of embryos showed that the lethality occurred between embryonic day 3.5 pc and 5.5 pc, a period of implantation and early development of implanted embryos. Two homozygous knockout mice that survived to term showed identical craniofacial defect, including a short snout and a round forehead. Examination of craniofacial morphology by measuring Snout Length (SL) vs. Face Width (FW) showed that the Cdk2ap1(+/-) mice were born with a reduced SL/FW ratio compared to the Cdk2ap1(+/+) and the reduction was more pronounced in Cdk2ap1(-/-) mice. A transgenic rescue of the lethality was attempted by crossing Cdk2ap1(+/-) animals with K14-Cdk2ap1 transgenic mice. Resulting Cdk2ap1(+/-:K14-Cdk2ap1) transgenic mice showed an improved incidence of full term animals (16.7% from 0.5%) on a Cdk2ap1(-/-) background. Transgenic expression of Cdk2ap1 in Cdk2ap1(-/-:K14-Cdk2ap1) animals restored SL/FW ratio to the level of Cdk2ap1(+/-:K14-Cdk2ap1) mice, but not to that of the Cdk2ap1(+/+:K14-Cdk2ap1) mice. Teratoma formation analysis using mESCs showed an abrogated in vivo pluripotency of Cdk2ap1(-/-) mESCs towards a restricted mesoderm lineage specification. This study demonstrates that Cdk2ap1 plays an essential role in the early stage of embryogenesis and has a potential role during craniofacial morphogenesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Lineage
  • Cyclin-Dependent Kinase 2 / antagonists & inhibitors
  • Embryo, Mammalian
  • Embryonic Development / genetics
  • Face / abnormalities*
  • Face / embryology
  • Genes, Lethal*
  • Genotype
  • Mesoderm
  • Mice
  • Mice, Mutant Strains
  • Morphogenesis / genetics*
  • Pluripotent Stem Cells / cytology
  • Protein Kinases / genetics*
  • Protein Kinases / physiology*
  • Skull / abnormalities*
  • Skull / embryology
  • Teratoma / genetics
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / physiology*


  • Tumor Suppressor Proteins
  • Protein Kinases
  • Cdk2ap1 protein, mouse
  • Cdk2 protein, mouse
  • Cyclin-Dependent Kinase 2