The role of an endogenous PKA inhibitor, PKIalpha, in organizing left-right axis formation.
Protein kinase inhibitor (PKI) is an endogenous inhibitor of cAMP-dependent protein kinase A (PKA). We have found that the alpha-isoform of PKI (PKIalpha) is asymmetrically expressed along the left-right (L-R) axis in chick embryos. At stage 6, PKIalpha is expressed on the right side of the node, and this asymmetric expression continues until stage 7+. After stage 8, PKIalpha expression returns symmetric. Treatment of embryos with antisense PKIalpha 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 PKIalpha on the left side of the node, while ectopic Shh and anti-Shh antibody had no effect on PKIalpha expression. Taken together, these data suggest that PKIalpha induced by an activin-like molecule, through the inhibition of PKA activity, suppresses the Nodal-Pitx2 pathway on the right side of the body.
Kawakami
M
M
The Burnham Institute, Center for Neuroscience and Aging, La Jolla, CA 92037, USA.
Nakanishi
N
N
D028341:Activins; D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002642:Chick Embryo; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D015870:Gene Expression; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins / Q000235:genetics; D007265:Inhibins / Q000378:metabolism; D055457:Nodal Protein; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D011506:Proteins / Q000235:genetics; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D000097577:Homeobox Protein PITX2
D028341:Activins; D002352:Carrier Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D007265:Inhibins; D055457:Nodal Protein; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D011506:Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000097577:Homeobox Protein PITX2