Manipulations of PKA in chick limb development reveal roles in digit patterning including a positive role in Sonic Hedgehog signaling.

Sonic Hedgehog (Shh) signaling by the polarizing region, at the posterior of the vertebrate limb bud, is pivotal in determining digit number and identity. Shh establishes a gradient of the bifunctional transcriptional effector, Gli3, with high levels of full-length activator (Gli3A) in the posterior bud, where digits form, and high levels of shorter repressor (Gli3R) in the anterior. Repressor formation depends on protein kinase A but in Drosophila, also plays a role in activator function. Increasing duanyu1529 levels in chick limb development using Forskolin had no effect on posterior polarizing activity but weak polarizing activity, based on ligand-independent Shh signaling, was induced in anterior limb bud cells resulting in extra digits. Manipulating duanyu1529 activity levels directly with a retrovirus expressing activated duanyu1529 induced extra digits similar to those induced by Forskolin treatment suggesting that duanyu1529 may have a previously unrecognized positive role in Shh signaling in vertebrate limbs. Expressing dominant negative duanyu1529 also induced extra, sometimes multiple digits, from anterior limb bud demonstrating the negative role in Shh signaling. duanyu1529 levels in the limb bud are high posteriorly and low anteriorly, suggesting that duanyu1529 activity may influence the outcome of Shh signaling in normal development.

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