Targeted inactivation of p12, CDK2 associating protein 1, leads to early embryonic lethality.
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.
Kim
Yong
Y
Division of Oral Biology and Medicine, Dental Research Institute, School of Dentistry, University of California Los Angeles, Los Angeles, California, United States of America.
McBride
Jim
J
Kimlin
Lauren
L
Pae
Eung-Kwon
EK
Deshpande
Amit
A
Wong
David T
DT
D000818:Animals; D019070:Cell Lineage; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000235:genetics; D005145:Face / Q000002:abnormalities* / Q000196:embryology; D005804:Genes, Lethal; D005838:Genotype; D008648:Mesoderm; D051379:Mice; D008817:Mice, Mutant Strains; D009024:Morphogenesis / Q000235:genetics*; D039904:Pluripotent Stem Cells / Q000166:cytology; D011494:Protein Kinases / Q000235:genetics* / Q000502:physiology*; D012886:Skull / Q000002:abnormalities* / Q000196:embryology; D013724:Teratoma / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology*
D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C496849:Cdk2ap1 protein, mouse; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2