Inducing regeneration in injured spinal cord represents one of modern medicine greatest challenges. Research from a variety of model organisms indicates that Hedgehog (Hh) signaling may be a useful target to drive regeneration. However, the mechanisms of Hedgehog signaling-mediated tissue regeneration remain unclear. Here we examined Hh signaling during post-amputation tail regeneration in Xenopus laevis larvae. We found that while Smoothened (Smo) activity is essential for proper spinal cord

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... d skeletal muscle regeneration, transcriptional activity of the canonical Hh effector Gli is repressed immediately following amputation, and inhibition of Gli1/2 expression or transcriptional activity has minimal effects on regeneration. In contrast, we demonstrate that protein kinase A (PKA) is necessary for regeneration of both muscle and spinal cord, in concert with and independent of Smo respectively, and that its downstream effector CREB is activated in spinal cord following amputation. Our findings indicate that non-canonical mechanisms of Hh signaling are necessary for spinal cord and muscle regeneration.