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J. Biol. Chem., Vol. 277, Issue 30, 27294-27304, July 26, 2002
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From the A targeted disruption of the RI
Increased Basal cAMP-dependent Protein Kinase
Activity Inhibits the Formation of Mesoderm-derived Structures in the
Developing Mouse Embryo*
,,,,,
, and§
Department of Pharmacology and the
Department of Medicine, University of Washington,
Seattle, Washington 98195 and the ¶ Department of Biochemistry,
University of North Carolina, Chapel Hill, North Carolina 27599
isoform of
protein kinase A (PKA) was created by using homologous recombination in
embryonic stem cells. Unlike the other regulatory and catalytic
subunits of PKA, RI is the only isoform that is essential for early
embryonic development. RI homozygous mutant embryos fail to develop
a functional heart tube at E8.5 and are resorbed at approximately
E10.5. Mutant embryos show significant growth retardation and
developmental delay compared with wild type littermates from E7.5 to
E10.5. The anterior-posterior axis of RI mutants is well developed, with a prominent head structure but a reduced trunk. PKA activity measurements reveal an increased basal PKA activity in these embryos. Brachyury mRNA expression in the primitive
streak of RI mutants is significantly reduced, consistent with later
deficits in axial, paraxial, and lateral plate mesodermal derivatives.
This defect in the production and migration of mesoderm can be
completely rescued by crossing RI mutants to mice carrying a
targeted disruption in the C catalytic subunit, demonstrating that
unregulated PKA activity rather than a specific loss of RI is
responsible for the phenotype. Primary embryonic fibroblasts from RI
mutant embryos display an abnormal cytoskeleton and an altered ability
to migrate in cell culture. Our results demonstrate that unregulated
PKA activity negatively affects growth factor-mediated mesoderm
formation during early mouse development.
*
This work was supported by National Institutes of Health
Grant GM32875 and by NICHD Grant U54-HD12629 from the National
Institutes of Health through cooperative agreement as part of the
Specialized Cooperative Centers Program in Reproduction Research.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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