DELAYED EMBRYONIC LETHALITY IN MICE LACKING PROTEIN PHOSPHATASE 2A CATALYTIC SUBUNIT C-ALPHA

Protein phosphatase 2A (PP2A) is a multimeric enzyme, containing a cat alytic subunit complexed with two regulatory subunits, The catalytic s ubunit PP2A C is encoded by two distinct and unlinked genes, termed C alpha and C beta. The specific function of these two catalytic subunit s is unknown. To address the possible redundancy between PP2A and rela ted phosphatases as well as between C alpha and C beta, the C alpha su bunit gene was deleted by homologous recombination. Homozygous null mu tant mice are embryonically lethal, demonstrating that the C alpha sub unit gene is an essential gene. As PP2A exerts a range of cellular fun ctions including cell cycle regulation and cell fate determination, we were surprised to find that these embryos develop normally until post implantation, around embryonic day 5.5/6.0. While no C alpha protein i s expressed, we find comparable expression levels of PP2A C at a time when the embryo is degenerating, Despite a 97% amino acid identity, C beta cannot completely compensate for the absence of C alpha. Degenera ted embryos can be recovered even at embryonic day 13.5, indicating th at although embryonic tissue is still capable of proliferating, normal differentiation is significantly impaired. While the primary germ lay ers ectoderm and endoderm are formed, mesoderm is not formed in degene rating embryos.