Ecto-domain phosphorylation promotes functional recovery from spinal cord injury.

Kenji Suehiro,Yoshinori Takei,Yoshiaki Yamaguchi,Shuai Xu,Hitoshi Okamura,Youichi Uda,Takafumi Matsumura,Yuka Nakamura,Toshihide Yamashita

doi:10.1038/srep04972

Kenji Suehiro, Yoshinori Takei + Show 7 more

Open Access

https://doi.org/10.1038/srep04972

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Abstract

Inhibition of Nogo-66 receptor (NgR) can promote recovery following spinal cord injury. The ecto-domain of NgR can be phosphorylated by protein kinase A (PKA), which blocks activation of the receptor. Here, we found that infusion of PKA plus ATP into the damaged spinal cord can promote recovery of locomotor function. While significant elongation of cortical-spinal axons was not detectable even in the rats showing enhanced recovery, neuronal precursor cells were observed in the region where PKA plus ATP were directly applied. NgR1 was expressed in neural stem/progenitor cells (NSPs) derived from the adult spinal cord. Both an NgR1 antagonist NEP1-40 and ecto-domain phosphorylation of NgR1 promote neuronal cell production of the NSPs, in vitro. Thus, inhibition of NgR1 in NSPs can promote neuronal cell production, which could contribute to the enhanced recovery of locomotor function following infusion of PKA and ATP.

Highlights

Inhibition of Nogo-66 receptor (NgR) can promote recovery following spinal cord injury
Nogo-66 receptor 1 (NgR1) was expressed in neural stem/progenitor cells (NSPs) derived from the adult spinal cord
These results indicate that protein kinase A (PKA)-mediated ecto-domain phosphorylation can increase production of neuronal cells from NSPs derived from adult spinal cord, via transient increase in oligodendrocyte transcription factor 2 (Olig2)-positive cells

Summary

Results

Effects of PKA and ATP on the damage from SCI. As described schematically in Fig. 1a, we performed a dorsal hemisection on the spinal cords of Wistar rats at the T9 vertebral level. Treatment with PKA plus ATP had no effects on the change of the total cell number in the course of differentiation (Fig. 4f) Taken together, these results indicate that PKA-mediated ecto-domain phosphorylation can increase production of neuronal cells from NSPs derived from adult spinal cord, via transient increase in Olig2-positive cells. The treatment had no effects on the percentage of beta III tubulin-positive cells differentiated from NSPs overexpressing the mutant NgR1 (Fig. 5c and d) These results indicate that phosphorylation of NgR1 is essential for promotion of neuronal cell production by co-treatment with PKA and ATP

Discussion

Methods

Additional information