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The role of an endogenous PKA inhibitor, PKI, in organizing left-right axis formation

Minoru Kawakami^* and Nobuki Nakanishi

The Burnham Institute, Center for Neuroscience and Aging, La Jolla, CA 92037, USA
Harvard Medical School, Department of Neurobiology, Boston, MA 02115, USA
^* Present address: The Queen’s Medical Center, Honolulu, HI 96813, USA

Author for correspondence (e-mail: nnakanishi{at}burnham.org)

Accepted April 12, 2001

Protein kinase inhibitor (PKI) is an endogenous inhibitor of cAMP-dependent protein kinase A (PKA). We have found that the -isoform of PKI (PKI) is asymmetrically expressed along the left-right (L-R) axis in chick embryos. At stage 6, PKI is expressed on the right side of the node, and this asymmetric expression continues until stage 7+. After stage 8, PKI expression returns symmetric. Treatment of embryos with antisense PKI oligonucleotides increased the incidence of reversed heart looping. Antisense oligonucleotides also induced ectopic expression of the left-specific genes Nodal and Pitx2, and suppressed the expression of the right-specific gene SnR in the right lateral plate mesoderm. Similarly, treatment with PKA activators forskolin and Sp-cAMPs resulted in both reversed heart looping and bilateral expression of Nodal. Ectopic activin induced PKI on the left side of the node, while ectopic Shh and anti-Shh antibody had no effect on PKI expression. Taken together, these data suggest that PKI induced by an activin-like molecule, through the inhibition of PKA activity, suppresses the Nodal-Pitx2 pathway on the right side of the body.

Key words: Left-right axis formation, Vertebrate, Embryogenesis, Patterning, Chick

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