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

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

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Division of Oral Biology and Medicine, Dental Research Institute, School of Dentistry, University of California Los Angeles, Los Angeles, California, United States of America.


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.

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