Abstract
Inducing regeneration in injured spinal cord represents one of modern medicine's 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 Hh 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 and 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 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 in a Smo-dependent manner. Our findings indicate that non-canonical mechanisms of Hh signaling are necessary for spinal cord and muscle regeneration.
Highlights
Injury in low regenerative capacity tissues such as spinal cord represents a persistent challenge in modern medicine, with millions of cases of spinal cord-related disability worldwide (Lee et al, 2014)
In addition, Ca2+-dependent activity is necessary for neuronal and muscle cell differentiation during embryonic skeletal muscle and spinal cord development (Borodinsky et al, 2004; Ferrari et al, 1996; Ferrari & Spitzer, 1999; Gu & Spitzer, 1995). This activity interacts with non86 canonical, Ca2+-dependent signaling. Treatment withSonic hedgehog (Shh) signaling during spinal cord neuron differentiation (Belgacem & Borodinsky, 2011), positioning non-canonical Hh signaling as an excellent candidate for regulating regeneration in muscle and neural tissues
We found that Ca2+ activity is associated with both muscle regeneration (Tu and Borodinsky, 2014) and protein kinase A (PKA)-dependent non-canonical Shh signaling through Smo during embryonic spinal cord development (Belgacem & Borodinsky, 2011, 2015)
Summary
Injury in low regenerative capacity tissues such as spinal cord represents a persistent challenge in modern medicine, with millions of cases of spinal cord-related disability worldwide (Lee et al, 2014). Hh binding represses its receptor Patched (Ptch), thereby de-repressing the G-protein coupled receptor Smo. Canonically, Smo activates the transcription factor Gli, which drives transcription of both Ptch and the positive feedback regulator Gli, as well as a wide variety of genes controlling cell migration, differentiation and especially proliferation (Briscoe & Therond, 2013). We found that Hh signaling is necessary for the regeneration of the spinal cord and skeletal muscle, primarily through Gli-independent pathways, and our results implicate PKA/CREB as an interacting signaling cascade. These findings offer the possibility of enhancing regeneration by differentially targeting canonical and non-canonical Hh pathways
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