Failure To Proliferate and Mitotic Arrest of CDK11^p110/p58-Null Mutant Mice at the Blastocyst Stage of Embryonic Cell Development

Abstract

The CDK11^p110 protein kinases are part of large-molecular-weight complexes that also contain RNA polymerase II, transcriptional elongation factors, and general pre-mRNA splicing factors. CDK11^p110 isoforms may therefore couple transcription and pre-mRNA splicing by their effect(s) on certain proteins required for these processes. The CDK11^p58 kinase isoform is generated from the CDK11^p110 mRNA through the use of an internal ribosome entry site in a mitosis-specific manner, suggesting that this kinase may regulate the cell cycle during mitosis. The in vivo role and necessity of CDK11^p110/p58 kinase function during mammalian development were examined by generating CDK11^p110/p58-null mice through targeted disruption of the corresponding gene using homologous recombination. While heterozygous mice develop normally, disruption of both CDK11^p110/p58 alleles results in early embryonic lethality due to apoptosis of the blastocyst cells between 3.5 and 4 days postcoitus. Cells within these embryos exhibit both proliferative defect(s) and a mitotic arrest. These results are consistent with the proposed cellular functions of the CDK11^p110/p58 kinases and confirm that the CDK11^p110/p58 kinases are essential for cellular viability as well as normal early embryonic development.

We thank Gerard Grosveld, director of Transgenic/Knockout Core, and Christie Nagy for their help and assistance in generating the knockout mice; we also thank Nagy for help with the isolation of blastocysts and Madoka Inoue for maintaining the mouse colonies and performing tail DNA analysis. We also acknowledge Susan Ragsdale and the SJCRH Cancer Center Cytogenetics Shared Resource for performing the karyotype analysis of the ES cell clones, and we thank Ken Barnes in the SJCRH Cancer Center Scientific Imaging Shared Resource for assistance performing the confocal microscopy. Finally, we thank Dongli Hu and Pascal Loyer for helpful discussions.

This research was supported by a grant from the NIH (2RO1 GM44088-13) to V.J.K., from the NIH to SJCRH (P30 CA21765-25) and by the generous support of the American Lebanese Syrian Associated Charities (ALSAC).