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Delayed embryonic lethality in mice lacking protein phosphatase 2A catalytic subunit Calpha
1Institut für Molekularbiologie, Abteilung I, Universität Zürich, Hönggerberg, 8093 Zurich, Switzerland. goetz@molbio1.unizh.ch
Abstract:
Protein phosphatase 2A (PP2A) is a multimeric enzyme, containing a catalytic subunit complexed with two regulatory subunits. The catalytic subunit PP2A C is encoded by two distinct and unlinked genes, termed Calpha and Cbeta. The specific function of these two catalytic subunits is unknown. To address the possible redundancy between PP2A and related phosphatases as well as between Calpha and Cbeta, the Calpha subunit gene was deleted by homologous recombination. Homozygous null mutant mice are embryonically lethal, demonstrating that the Calpha subunit gene is an essential gene. As PP2A exerts a range of cellular functions including cell cycle regulation and cell fate determination, we were surprised to find that these embryos develop normally until postimplantation, around embryonic day 5.5/6.0. While no Calpha protein is expressed, we find comparable expression levels of PP2A C at a time when the embryo is degenerating. Despite a 97% amino acid identity, Cbeta cannot completely compensate for the absence of Calpha. Degenerated embryos can be recovered even at embryonic day 13.5, indicating that although embryonic tissue is still capable of proliferating, normal differentiation is significantly impaired. While the primary germ layers ectoderm and endoderm are formed, mesoderm is not formed in degenerating embryos.
Insights
The Calpha gene is essential for embryonic development, as its deletion causes lethality. Even with Cbeta expression, the absence of Calpha impairs normal differentiation and mesoderm formation in developing embryos.
Area of Science:
- Molecular Biology
- Developmental Biology
- Biochemistry
Background:
- Protein phosphatase 2A (PP2A) is a crucial enzyme involved in various cellular functions.
- PP2A comprises catalytic and regulatory subunits; the catalytic subunit PP2A C is encoded by Calpha and Cbeta genes.
- The distinct roles of Calpha and Cbeta catalytic subunits remain largely unknown.
Purpose of the Study:
- To investigate the functional redundancy between Calpha and Cbeta catalytic subunits of PP2A.
- To determine the essentiality of the Calpha subunit gene in embryonic development.
Main Methods:
- Homologous recombination was used to delete the Calpha subunit gene in mice.
- Homozygous null mutant mice were analyzed for embryonic development and protein expression.
Main Results:
- Homozygous Calpha null mutant mice are embryonically lethal, indicating the gene's essential role.
- Embryos lacking Calpha develop normally until postimplantation (around day 5.5/6.0) but then degenerate.
- Despite high similarity, the Cbeta subunit cannot fully compensate for Calpha absence, leading to impaired differentiation and lack of mesoderm formation.
Conclusions:
- The Calpha subunit gene is indispensable for mammalian embryonic development.
- Cbeta cannot completely substitute for Calpha function, highlighting specific roles for each catalytic subunit.
- Absence of Calpha severely impacts embryonic differentiation, particularly mesoderm development.
